Masters Degree in Antibiotic Discussion

DQ 10. Create your initial post on the DQ 10 Discussion Board in response to the following questions:Each student should post an example of a protein synthesis inhibitor (30S or 50S inhibitor) that was NOT discussed in the lecture videos. EACH POSTING SHOULD BE DIFFERENT, FIRST COME-FIRST SERVED. You may post a note to “claim” an antibiotic before beginning your research for your complete posting. You may post an example from the non-textbook readings, an analog of one of the antibiotics which was not discussed in class, or an example from another reliable source. The post should include the following:Antibiotic nameUse (or “in development”)Mechanism of action (specific)Current status (e.g. “not used medically – why?, toxicity?, resistance?” or “currently in development – what makes it better than current drugs?”)Information source(s) Course Overview
Advanced Topics -‐ An4bio4cs
Professor: Gregory Caputo
Oﬃce: 130C Science Hall
Phone: 256-‐5453
Email: caputo@rowan.edu
OFFICE HOURS: by appointment

Professor: Lark Perez
Oﬃce: 301B Science Hall
Phone: 256-‐4502
Email: perezla@rowan.edu
OFFICE HOURS: by appointment

Course outline
1
3
Introduc8on to and overview of market and industry demands; General aspects of
an8bio8c drug development
Introduc8on to bacterial physiology; an8bacterial methods, an8microbial
resistance
History of an8bio8cs, Intro to classes of an8bacterials
4
β-‐lactams, vancomycin; Mechanism of cell wall inhibitors
5
Inhibitors of protein synthesis; Aminoglycosides and Streptomycin; Tetracyclines;
Mechanism of 30S transla8onal inhibitors.
Inhibitors of Protein Synthesis, con8nued. Chloramphenicol and Macrolides;
Mechanism of 50S transla8onal inhibitors.
Synthe8c approaches to sulfonamides, trimethoprim; Mechanism of metabolic
inhibitors; Synthe8c approaches to quinolones and rifamycin; Mechanism of DNA/
RNA polymerase inhibitors
2
6
7
8
Alterna8ve Approaches to an8microbial development -‐ Pep8des &
proteins; Polymers & mime8cs; Phage Therapy; Quorum Sensing
Inhibitors
Texts and Reference Material
• Book: Claudio O. Gualerzi, Le4zia Brandi, AUlio FabbreU, Cynthia L.
Pon (Eds.) An4bio4cs: Targets, Mechanisms and Resistance, Wiley-‐
VCH, 2014. (recommended, not required)
• Assigned Journal ar8cles
– All should be accessible via Rowan’s library subscrip4ons
– Inaccessible ar4cles will be provided

• Other texts:
– Nelson & Cox, Lehninger Principles of Biochemistry, 5th edi=on, W.H.
Freeman Company
– Brown, Foote, Iverson, and Anslyn Organic Chemistry, Brooks Cole,
2004/2010;
– Willey, Sherwood and Woolverton, PrescoD’s Microbiology, McGraw-‐
Hill
Quizzes
• Roughly once per week
• Mul4ple choice format online
• Due by Friday of each week
Exams
• Each exam covers ~50% of the course material
• Second exam is cumula4ve with extra
emphasis on the second half of the course
• Exams are online, mul4ple choice.
• Exam must be completed by Friday, July 24,
11:59PM
Paper
• In depth discussion of an an4bio4c that is ON the
market or in clinical trials
• Should include:
– Discovery
– Synthesis/puriﬁca4on
– Mechanism of ac4on
– Applica4ons
– Market analysis
• Topic should be approved by 6/22/2015 (week 4)
Paper
• 2500 WORD limit.
• Single spaced
• Font: 12, Times New Roman
• No limit on ﬁgures/illustra4ons
• Fully referenced using An4microbial Agents &
Chemotherapy format (references do not
count in word limit).

An#microbial Market and
Industry
An#bio#cs – The need
• An#bio#cs are one of the most commonly
prescribed forms of medica#on
• Designed to ﬁght BACTERIAL infec#ons
– Note, there are an#virals, an#fungals, etc. however
the term ANTIBIOTICS generally refers to an#bacterial
agents
• Drugs designed to kill bacteria are eﬀec#vely
useless against non-‐bacterial targets
• The term “an#bio#c” was coined in 1942 by
Selman Waksman
What do an#bio#cs ﬁght?
• Bacteria.
• Before we talk about that, a quick word on
nomenclature
– Bacterial naming uses a BINOMIAL system
– A species name has 2 parts:
• Genus name
• Species epithet
Staphylococcus Aureus
S. Aureus
What do an#bio#cs ﬁght?
• Pertussis aka whooping cough (Bordetella pertussis)
• Bacterial Pneumonia (Klebsiella pneumoniae,
Streptococcus pneumoniae, among others.)
• Plague (Yersinia pes:s)
• Chlamydia (Chlamydia trachoma:s)
• Lyme Disease (Borrelia Burgdorferi)
• Typhoid fever (Salmonella)
• Wound-‐site infec#ons (numerous)
• Lots more!
Early history of An#bio#cs
• Greeks and Indians used molds and other plants to
treat infec#ons.
• In Greece and Serbia, moldy bread was tradi#onally
used to treat wounds and infec#ons.
• Warm soil was used in Russia by peasants to cure
infected wounds.
• Sumerian doctors gave pa#ents beer soup mixed with
turtle shells and snake skins.
• Babylonian doctors healed the eyes using a mixture of
frog bile and sour milk.
• Sri Lankan army used oil cake (sweetmeat) to serve
both as desiccant and an#bacterial
More modern ﬁndings
1640 England
1870 England
1871 England
1875 England
1877 France
1897 France
1928 England
1932 Germany
John Parkington recommended using mold for treatment in his
book on pharmacology
Sir John Scoa Burdon-‐Sanderson observed that culture ﬂuid
covered with mould did not produce bacteria
Joseph Lister experimented with the an#bacterial ac#on on human
#ssue on what he called Penicillium glaucium
John Tyndall explained an#bacterial ac#on of the Penicillium
fungus to the Royal Society
Louis Pasteur postulated that bacteria could kill other bacteria
(anthrax bacilli)
Ernest Duchesne healed infected guinea pigs from typhoid using
mould (Penicillium glaucium)
Sir Alexander Fleming discovered enzyme lysozyme and the
an#bio#c substance penicillin from the fungus Penicillium notatum
Gerhard Domagk discovered Sulfonamidochrysoidine (Prontosil )
Alexander Fleming
• Scogsh physician with a speciﬁc interest in
microbial infec#ons
• Served as a baaleﬁeld doctor during WWI
which further drove him to study an#bio#cs
• Credited for discovering penicillin, a
compound produced by mold that kills
bacteria
• Nobel Prize in Physiology or Medicine 1945
“One some#mes ﬁnds what one is not
looking for.”
Selman Waksman
• Biochemist/microbiologist at Rutgers
• His group discovered several an#bio#cs:
ac#nomycin, clavacin, streptothricin,
streptomycin, grisein, neomycin, fradicin,
candicidin, candidin.
• Streptomycin and neomycin are widely used
• Nobel Prize in Physiology or Medicine 1945
So why are we even talking about this?
• An#bio#cs are one of the most ubiquitously
prescribed medicines in the world.
Figure 1
Figure 2
The Lancet Infectious Diseases 2014 14, 742-750DOI: (10.1016/S1473-3099(14)70780-7)
Transla#on – big bu$ine$$
• “The an#bio#cs market generated sales of US
$42 billion in 2009 globally, represen#ng 46%
of sales of an#-‐infec#ve agents (which also
include an#viral drugs and vaccines) and 5% of
the global pharmaceu#cal market”
So why are we even talking about this?
• An#bio#cs are one of the most ubiquitously
prescribed medicines in the world.
• But it’s not inﬁnite
• Some bacteria are insensi#ve to certain
an#bio#cs by nature
• Some microorganisms can develop
RESISTANCE.
Oh….
• We’re outnumbered
– Es#mates put ~ 5×1030 bacteria on Earth (only
8×109 people)
– There are 10 bacteria in your intes#nes for every 1
of your cells.
• They’re faster than us
– Bacteria can replicate in as liale as 20 minutes
– 1 cell infected with inﬂuenza will produce ~20
new ﬂu viruses 11h later (~ 30 minutes per virus)
Well, at least we know how to
discover drugs
• Yes, but not so fast.
• For decades, major pharmaceu#cal companies
abandoned their an#bio#c pipelines.
• The CO$T of developing an an#bio#c was
greater than the proﬁt margin, especially since
– most are covered by insurance
– emerging resistance could curtail usefulness of a
given drug
And the resistance is coming
• Exis#ng an#bio#cs are becoming obsolete
• Surveillance indicates more and more strains
are becoming resistant to “blockbuster” or
“last-‐line” an#bio#cs
Summary
• An#bio#cs have been used in various forms
throughout history
• The modern study of an#bio#cs took oﬀ in the
last 100 years
• Current an#bio#cs are becoming obsolete due
to resistance
• The pipeline is nearly dry because of business
+ resistance issues
References
•
•
•
•
•
hap://dx.doi.org/10.1016/S1473-‐3099(14)70780-‐7
Tcichemicals.com
drugs.com
doi:10.1038/nrd3267
IMS Health. IMS MIDAS (2009).
Drug Discovery
With an emphasis on Antibiotics
caputo@rowan.edu
Drug Discovery
• Process by which new candidate
medications are identiﬁed
• Can stem from natural sources or laboratory
created molecules
• Direct ties to patient health but also a huge
driver of biomedical research
So, how do we discover drugs?
Natural Products
• Many current drugs were discovered by
analyzing natural products
• These can be direct extracts from biological
materials OR synthetic replicas
Natural Products
• Many current drugs were discovered by
analyzing natural products
• These can be direct extracts from biological
materials OR synthetic replicas
So, how do we discover drugs now?
• Academic and industrial R&D
– R&D = Research & Development
• Two philosophical approaches
– Identify a speciﬁc target/disease/condition and
rationally design systems to target
– Develop molecular libraries and broadly test for
activity using High Throughput Screening (HTS)

Known Target Approach
• Requires a thorough understanding of HOW
the disease works and WHAT goes wrong to
cause it
Known Target Approach
• Requires a thorough understanding of HOW
the disease works and WHAT goes wrong to
cause it
• Usually requires a combination of chemistry,
biochemistry, cell biology, and physiology to
make informed decisions in development
High Throughput Screening
Approach
• Requires huge libraries of compounds
• Requires access to a variety of cell/tissue
reporter systems
• Often done using automation
High Throughput Screening
Approach
• Requires huge libraries of compounds
• Requires access to a variety of cell/tissue
reporter systems
• Often done using automation
• Actually a ﬁshing expedition.
• Requires extensive follow up
experimentation
HTS Video – 26:14
Let’s not forget in silico screening
• Virtual screening/design can aid both
approaches
• Two approaches
– Ligand Based – build a model of a target based
on what binds to it
– Structure Based – build ligands based on the
structure of the target
Ligand Based
?
Structure Based
How does virtual screening work?
• Based on interaction ENERGY
• Atomic and molecular interactions
determine if a given interaction is favorable
or unfavorable
– Electrostatics (charges)
– Van der waals (size of molecules/atoms)
– Hydrogen bonds
MD Video
MD Video 2
OK, so what’s the problem?
• If we know HOW to discover drugs, then
why do we still get sick?
OK, so what’s the problem?
• If we know HOW to discover drugs, then
why do we still get sick?
– Long, costly approval process
– Side eﬀects
– Eﬃcacy diﬀerences based on genetics
– Resistance!
Clinical Trials
• Necessary, but costly
• Designed to ensure safety & eﬃcacy of
drugs while also identifying unknown
complicating factors
• EXTENSIVELY regulated by the FDA
Clinical Trials
• Broken down into phases
– Phase 0: Drug discovery and “pre-‐clinical”
– Phase 1: Screening for safety
– Phase 2: Establishing the eﬃcacy of the drug,
usually against a placebo
– Phase 3: Final conﬁrmation of safety and eﬃcacy
– Phase 4: Sentry studies during sales
• Drugs are “approved after Phase3, but still
monitored
Clinical Trials
• From 1997-‐2011, drug companies spent $802
BILLION on clinical trials.
• For 139 drugs.
• Translates to $5.8 BILLION per drug (just on
the trials!)
• “Phase III trials now represent about 40
percent of pharmaceutical companies’ R&D
expenditures”
It’s not perfect
Adderall XR
2005
Risk of stroke[1] The ban was later lifted because the death rate among those taking Adderall XR was determined to be no greater than those not taking Adderall.
Alatroﬂoxacin
2006
Liver toxicity; serious liver injury leading to liver transplant; death.[2]
1979
Vasculitis, Rash.[3]
1995
Not approved in the US, withdrawn in France in 1994[4] and the rest of the market in 1995 because of rare but serious hepatotoxicity.[3][5]
Alclofenac
Alpidem (Ananxyl)
Alosetron (Lotronex)
2000
Serious gastrointestinal adverse events; ischemic colitis; severe constipation.[2] Reintroduced 2002 on a restricted basis[citation needed]
Althesin (=Alphaxolone amineptine + Alphadolone)
1984
Anaphylaxis.[3]
Amineptine (Survector)
1999
Hepatotoxicity, dermatological side eﬀects, and abuse potential.[6] Reason:
Aminopyrine
1999
Abuse; dependence; severe acne.[3]
Amobarbital
1980
Self poisoning.[3]
Amoproxan
1970
Dermatologic and ophthalmic toxicity.[3]
Anagestone acetate
1969
Animal carcinogenicity.[3]
Antrafenine
1984
Unspeciﬁc experimental toxicity.[3]
Aprotinin (Trasylol)
2008
Increased risk of death.[2]
Ardeparin (Normiﬂo)
2001
Not for reasons of safety or eﬃcacy.[7]
Astemizole (Hismanal)
1999
Fatal arrhythmia[2][3]
Azaribine
1976
Thromboembolism.[3]
Bendazac
1993
Hepatotoxicity.[3]
Benoxaprofen
1982
Liver and kidney failure; gastrointestinal bleeding; ulcers.[2][3]
Benzarone
1992
Hepatitis.[3]
Benziodarone
1964
Jaundice.[3]
Beta-‐ethoxy-‐lacetanilanide
1986
Renal toxicity, animal carcinogenicity.[3]
Bezitramide
2004
Fatal overdose.[8]
Bithionol
1967
Dermatologic toxicity.[3]
Broazolam
1989
Animal carcinogenicity.[3]
Bromfenac
1998
Severe hepatitis and liver failure (some requiring transplantation).[2]
Bucetin
1986
Renal toxicity.[3]
Buformin
1978
Metabolic toxicity.[3]
Bunamiodyl
1963)
Nephropathy.[9]
Butamben (Efocaine)(Butoforme)
1964
Dermatologic toxicity; psychiatric Reactions.[3]
Canrenone
1986
Animal Carcinogenicity.[3]
Cerivastatin (Baycol, Lipobay)
2001
Risk of rhabdomyolysis[2]
Chlormadinone (Chlormenadione)
1970
Animal Carcinogenicity.[3]
Chlormezanone (Trancopal)
1996
Hepatotoxicity; Steven-‐Johnson Syndrome; Toxic Epidermal Necrolysis.[3]
Chlorphentermine
1969
Cardiovascular Toxicity.[3]
Cianidanol
1985
Hemolytic Anemia.[3]
Cinepazide
1987
Agranulocytosis.[3]
Cisapride (Propulsid)
2000
Risk of fatal cardiac arrhythmias[2]
Clioquinol
1973
Neurotoxicity.[3]
Clobutinol
2007
Ventricular arrhythmia, QT-‐prolongation.[10]
Cloforex
1969
Cardiovascular toxicity.[3]
Clomacron
1982
Hepatotoxicity.[3]
Clometacin
1987
Hepatotoxicity.[3]
Co-‐proxamol (Distalgesic)
2004
Overdose dangers.
Cyclobarbital
1980
Self poisoning.[3]
Cyclofenil
1987
Hepatotoxicity.[3]
Dantron
1963
Genotoxicity.[11]
Dexfenﬂuramine
1997
Cardiac valvular disease.[3]
Propoxyphene (Darvocet/Darvon)
2010
Increased risk of heart attacks and stroke.[12]
Diacetoxydiphenolisatin
1971
Hepatotoxicity.[3]
Diethylstilbestrol
1970s
Risk of teratogenicity[citation needed]
Difemerine
1986
Multi-‐Organ toxicities.[3]
Dihydrostreptomycin
1970
Neuropsychiatric reaction.[3]
Dilevalol
1990
Hepatotoxicity.[3]
Dimazol (Diamthazole)
1972
Neuropsychiatric reaction.[3]
Dimethylamylamine (DMAA)
1983
Voluntarily withdrawn from market by Lily.[13]:12 Reintroduced as a dietary supplement in 2006;[13]:13 and in 2013 the FDA started work to ban it due to cardiovascular problems[14]
Dinoprostone
1990
Uterine hypotonus, fetal distress.[3]
Dipyrone(Metamizole)
1975
Agranulocytosis, anaphylactic reactions.[3]
Dithiazanine iodide
1964
Cardiovascular and metabolic reaction.[3]
Dofetilide
2004
Drug intereactions, prolonged QT.[10]
Drotrecogin alfa (Xigris)
2011
Lack of eﬃcacy as shown by PROWESS-‐SHOCK study[citation needed]
Ebrotidine
1998
Hepatotoxicity.[3]
Efalizumab (Raptiva)
2009
Withdrawn because of increased risk of progressive multifocal leukoencephalopathy[10]
Encainide
1991
Ventricular arrhythmias.[2][3]
Ethyl carbamate
1963
Carcinogenicity.[15]
Etretinate
1989
Withdrawn U.S. (1999). Risk for birth defects.[2][3]
Exifone
1989
Hepatotoxicity.[3]
Fen-‐phen (popular combination of fenﬂuramine and phentermine)
1997
Cardiotoxicity
Fenclofenac
1984
Cutaneous reactions; animal carcinogenicity.[3]
Fenclozic acid
1970
Jaundice, elevated hepatic enzymes.[3]
Fenﬂuramine
1997
Cardiac valvular disease, pulmonary hypertension, cardiac ﬁbrosis.[3][16]
Fenoterol
1990
Asthma mortality.[3]
Feprazone
1984
Cutaneous reaction, multiorgan toxicity.[3]
Fipexide
1991
Hepatotoxicity.[3]
Flosequinan (Manoplax)
1993
Increased mortality at higher doses; increased hospitalizations.[2][3]
Flunitrazepam
1991
Abuse.[3]
Gatiﬂoxacin
2006
Increased risk of dysglycemia.[2]
Gemtuzumab ozogamicin (Mylotarg)
2010
No improvement in clinical beneﬁt; risk for death.[2]
Glafenine
1984
Anaphylaxis.[3]
Grepaﬂoxacin (Raxar)
1999
Cardiac repolarization; QT interval prolongation.[2]
Hydromorphone (Palladone)]
2005
High risk of accidental overdose when administered with alcohol
Ibufenac
1968
Hepatotoxicity, jaundice.[3]
Indalpine
1985
Agranulocytosis.[3]
Indoprofen
1983
Animal carcinogenicity, gastrointestinal toxicity.[3]
Iodinated casein strophantin
1964
Metabolic reaction.[3]
Iproniazid
1964
Interactions with food products containing tyrosine.[17]
Isaxonine phosphate
1984
Hepatotoxicity.[3]
Isoxicam
1983
Stevens johnson syndrome.[3]
Kava Kava
2002
Hepatotoxicity.[10]
Ketorolac
1993
Hemorrhage, renal Failure.[3]
L-‐tryptophan
1989
Eosinophilic myalgia syndrome.[3]
Levamisole (Ergamisol)
1999
Still used as veterinary drug; in humans was used to treat melanoma before it was withdrawn for agranulocytosis
Levomethadyl acetate
2003
Cardiac arrhythmias and cardiac arrest.[2]
Lumiracoxib (Prexige)
2007–2008
Liver damage
Lysergic acid diethylamide (LSD)
1950s–1960s
Marketed as a psychiatric drug; withdrawn after it became widely used recreationally
Mebanazine
1975
Hepatotoxicity, drug intereaction.[3]
Methandrosteronolone
1982
Oﬀ-‐label abuse.[3]
Methapyrilene
1979
Animal carcinogenicity.[3]
Methaqualone
1984
Withdrawn because of risk of addiction and overdose[18][19]
Metipranolol
1990
Uveitis.[3]
Metofoline
1965
Unspeciﬁc experimental toxicity.[3]
Mibefradil
1998
Fatal arrhythmia, drug interactions.[2][3]
Mibefradil (Posicor)
1998
Withdrawn because of dangerous interactions with other drugs
Minaprine
1996
Convulsions.[3]
Moxisylyte
1993
Necrotic hepatitis.[3]
Muzolimine
1987
Polyneuropathy.[3]
Natalizumab (Tysabri)
2005–2006
Nefazodone
2007
Voluntarily withdrawn from U.S. market because of risk of Progressive multifocal leukoencephalopathy (PML). Returned to market July, 2006.
Branded version withdrawn by originator in several countries in 2007 for hepatotoxicity. Generic versions available.[20]
Nialamide
1974
Hepatotoxicity, drug intereaction.[3]
Nikethamide
1988)
CNS Stimulation.[3]
Nitrefazole
1984)
Hepatic and hematologic toxicity.[3]
Nomifensine
1981-‐1986
Oxeladin
1976
Oxyphenbutazone
1984-‐1985
Oxyphenisatin (Phenisatin)
Ozogamicin
Hemolytic Anemia, hepatotoxicity, serious hypersensitive reactions.[2][3]
Carcinogenicity.[21]
Bone marrow suppression, Steven Johnson Syndrome.[3][22]
Hepatotoxicity.[3]
2010
No improvement in clinical beneﬁt; risk for death; veno-‐occlusive disease.[2]
Pemoline (Cylert)
1997
Withdrawn from U.S in 2005. Hepatotoxicity[23] Reason:hepatotoxicity.[3]
Pentobarbital
1980
Self poisoning.[3]
Pentylenetetrazol
1982
Withdrawn for inability to produce eﬀective convulsive therapy, and for causing seizures.
Pergolide (Permax)
2007
Risk for heart valve damage.[2]
Perhexilene
1985
Neurologic and hepatic toxicity.[3]
Phenacetin
1975
An ingredient in “A.P.C.” tablet; withdrawn because of risk of cancer and kidney disease[24] Germany Denmark, U.K, U.S, others Reason: nephropathy.[3]
Phenformin and Buformin
1977
Severe lactic acidosis[3]
Phenolphthalein
1997
Carcinogenicity.[25]
1966
Hepatotoxicity, drug intereaction.[3]
Phenylbutazone
1985
Oﬀ-‐label abuse, hematologic toxicity.[3]
Phenylpropanolamine(Propagest, Dexatrim)
2000
Hemorrhagic stroke.[26][27]
Pifoxime (=Pixifenide)
Phenoxypropazine
1976
Neuropsychiatric reaction.[3]
Pirprofen
1990
Gastrointestinal toxicity.[3]
Prenylamine
1988
Cardiac arrythmia[28] and death.[3]
Proglumide
1989
Respiratory reaction.[3]
Pronethalol
1965
Animal carcinogenicity.[3]
Propanidid
1983
Allergy.[3]
Proxibarbal
1998
Immunoallergic, thrombocytopenia.[3]
Pyrovalerone
1979
Abuse.[3]
Rapacuronium (Raplon)
2001
Withdrawn in many countries because of risk of fatal bronchospasm[2]
Remoxipride
1993
Aplastic anemia.[3]
Rimonabant (Acomplia)
2008
Risk of severe depression and suicide[10]
Rofecoxib (Vioxx)
2004
Risk of myocardial infarction and stroke[2]
Rosiglitazone (Avandia)
2010
Secobarbital
Sertindole
Risk of heart attacks and death. This drug continues to be available in the U.S.
Self poisoning.[3]
1998
Arrhythmia and sudden cardiac death[3][29]
Sibutramine (Reductil/Meridia)
2010
Increased risk of heart attack and stroke.[2]
Sitaxentan
2010
Hepatotoxicity.[10]
Sorivudine
1993
Drug interaction and deaths.[citation needed]
Sparﬂoxacin
2001
QT prolongation and phototoxicity.[2]
Sulfacarbamide
1988
Dermatologic, hematologic and hepatic reactions .[3]
Sulfamethoxydiazine
1988
Unknown.[3]
Sulfamethoxypyridazine
1986
Dermatologic and hematologic reactions.[3]
Suloctidyl
1985
Suprofen
1986-‐1987
Tegaserod (Zelnorm)
2007
Risk for heart attack, stroke, and unstable angina.[2] Was available through a restricted access program until April 2008.
Temaﬂoxacin
1992
Low blood sugar; hemolytic anemia; kidney, liver dysfunction; allergic reactions[2][3]
Temaﬂoxacin
1992
Allergic reactions and cases of hemolytic anemia, leading to three patient deaths.[2]
Temazepam (Restoril, Euhypnos, Normison, Remestan, Tenox, Norkotral)
1999
Diversion, abuse, and a relatively high rate of overdose deaths in comparison to other drugs of its group. This drug continues to be available in most of the world including the U.S., but under strict controls.
Terfenadine (Seldane, Triludan)
1997-‐1998
Terodiline (Micturin)
1991
Prolonged QT interval, ventricular tachycardia and arrhythmia.[3]
2013
Serious cutaneous reactions.[41]
Tetrazepam
Hepatotoxicity.[3]
Flank pain, decreased kidney function.[2][3]
Prolonged QT interval; ventricular tachycardia[2][3]
Thalidomide
1961
Withdrawn because of risk of teratogenicity;[42] returned to market for use in leprosy and multiple myeloma under FDA orphan drug rules
Thenalidine
1960
Neutropenia[3][43]
Thiobutabarbitone
1993
Renal insuﬃciency.[3]
Thioridazine (Melleril)
2005
Withdrawn from U.K. market because of cardiotoxicity[10]
Ticrynafen(Tienilic acid)
1980
Liver toxicity and death.[3]
Tolcapone (Tasmar)
1998
Hepatotoxicity[3]
Tolrestat (Alredase)
1996
Severe hepatotoxicity[3]
Triacetyldiphenolisatin
1971
Hepatotoxicity.[3]
Triazolam
1991
Psychiatric adverse drug reactions, amnesia.[3][44]
Triparanol
1962
Cataracts, alopecia, ichthyosis.[3]
Troglitazone (Rezulin)
2000
Trovaﬂoxacin (Trovan)
1999-‐2001
Valdecoxib (Bextra)
2004
Risk of heart attack and stroke.[2]
Vincamine
1987
Hematologic toxicity.[3]
Xenazoic acid
1965
Hepatotoxicity.[3]
Ximelagatran (Exanta)
2006
Hepatotoxicity[10]
Zimelidine
1983
Hepatotoxicity[2]
Risk of Guillain-‐Barré syndrome, hypersensitivity reaction, hepatotoxicity[3][45][46] banned worldwide.[47]
Zomepirac
1983
Anaphylactic reactions and non-‐fatal allergic reactions, renal failure[2][3]
Withdrawn because of risk of liver failure[2][3]
That sucks. So why bother?
$$$$
(oh yeah, and to make people feel better)
Drug & Maker
Abilify
1 Otsuka Pharmaceu>cal Co.
Nexium
2 AstraZeneca Pharmaceu>cals, LP
Humira
3 AbbVie, Inc.
Crestor
4 AstraZeneca Pharmaceu>cals, LP
Cymbalta
5 Eli Lilly and Company
Advair Diskus
6 GlaxoSmithKline
Enbrel
7 Amgen Inc.
Remicade
8 Centocor Ortho Biotech, Inc
Copaxone
9 Teva Pharmaceu>cals
Neulasta
10 Amgen Inc.
Total sales
2013 Sales
$ 6,293,801,000.00
$ 5,974,550,000.00
$ 5,428,479,000.00
$ 5,195,930,000.00
$ 5,083,111,000.00
$ 4,981,108,000.00
$ 4,585,701,000.00
$ 3,980,556,000.00
$ 3,603,958,000.00
$ 3,472,969,000.00
$ 48,600,163,000.00
Drug & Maker
Abilify
1 Otsuka Pharmaceu>cal Co.
Nexium
2 AstraZeneca Pharmaceu>cals, LP
Humira
3 AbbVie, Inc.
Crestor
4 AstraZeneca Pharmaceu>cals, LP
Cymbalta
5 Eli Lilly and Company
Advair Diskus
6 GlaxoSmithKline
Enbrel
7 Amgen Inc.
Remicade
8 Centocor Ortho Biotech, Inc
Copaxone
9 Teva Pharmaceu>cals
Neulasta
10 Amgen Inc.
Total sales
2013 Sales
$ 6,293,801,000.00
$ 5,974,550,000.00
$ 5,428,479,000.00
$ 5,195,930,000.00
$ 5,083,111,000.00
$ 4,981,108,000.00
$ 4,585,701,000.00
$ 3,980,556,000.00
$ 3,603,958,000.00
$ 3,472,969,000.00
$ 48,600,163,000.00
Perspective: Rowan’s annual operating budget is ~$200 Million. That means sales from
Abilify could have supported ~31 Rowan Universities.
Image references
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
https://suite.io/sharon-‐falsetto/14w12e8
http://www.acuhhs.com/wp-‐content/uploads/bigstock-‐Natural-‐Medicine-‐Still-‐Life-‐7509941.jpg
http://traditionalmedicineinperuandes.weebly.com/herbal-‐and-‐plant-‐knowledge.html
https://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=https%3A%2F
%2Fﬁndingstrengthtostandagain.wordpress.com%2F2011%2F04%2F26%2Flessons-‐from-‐the-‐willow-‐tree
%2F&ei=mnr4VLDNFe_dsASyqoLQCg&bvm=bv.
87519884,d.cWc&psig=AFQjCNE3KrViKFYrIswp37rk1FIf_VgWzQ&ust=1425656855566964
http://www.stopcoloncancernow.com/spread-‐awareness/news/pain-‐relievers-‐may-‐also-‐relieve-‐chances-‐of-‐developing-‐colon-‐cancer
http://www.google.com/imgres?imgurl=http%3A%2F%2Fwww.jcda.ca%2Fuploads%2Fa35%2Fﬁg3.png&imgrefurl=http%3A%2F
%2Fwww.jcda.ca%2Farticle%2Fa35&h=486&w=600&tbnid=4KcM1EFuDvOi7M
%3A&zoom=1&docid=CXl_960SJbz_IM&ei=EK0BVMmbJ83JsQTqsIKACA&tbm=isch&client=ﬁrefox-‐
a&ved=0CB8QMygBMAE&iact=rc&uact=3&dur=1539&page=1&start=0&ndsp=24
http://scs.illinois.edu/htsf/
http://henskelab.org/
www.embl.de
http://imaging.bme.ucdavis.edu/overview-‐2/image-‐gallery/
http://www.lookfordiagnosis.com/mesh_info.php?term=High-‐Throughput+Screening+Assays&lang=1
www.slidegeeks.com/powerpoint-‐slides/38596-‐
business_funnels_powerpoint_templates_strategy_drug_discovery_process_ppt_slides/
https://www.google.com/imgres?imgurl&imgrefurl=http%3A%2F%2Fwww.immunetrics.com%2Fapplications%2Fdrug-‐
discovery.php&h=0&w=0&tbnid=4eLf7CXm1PnOEM&zoom=1&tbnh=152&tbnw=331&docid=CfqtYFTL3gcvVM&tbm=isch&client=ﬁr
efox-‐a&ei=y6wBVKO8I6K-‐sQSQrYLACQ
http://www.veteranstoday.com/2013/06/15/sarcomas-‐and-‐hope-‐for-‐veterans-‐exposed-‐to-‐agent-‐orange-‐and-‐du/clinical-‐trials/
http://www.drugs.com/stats/top100/2013/sales
Bacterial Physiology
caputo@rowan.edu
“So it is said that if you know your
enemies and know yourself, you can
win a hundred ba>les without a
single loss.”
-‐Sun Tzu
Know your enemy
• Before we can approach developing new and
be>er anEbioEcs, we have to understand the
target
• This is more diﬃcult than it sounds since there
are so many bacteria that cause disease
What ARE bacteria?
• Single celled organisms
– Prokaryotes
• Contain all the “normal” things you’d ﬁnd in cells
– Nucleic Acids (DNA, RNA)
– Proteins (Enzymes, acEvators, etc)
– Lipids (cell membrane)
– Carbohydrates (metabolism, cell surface)
– Small molecules & ions (ATP, Phosphates, Calcium, etc)
• DO NOT have organelles
Fig. 1-3
1. Compartmentalization and metabolism
Cells take up nutrients from the environment, transform them,
and release wastes into the environment. The cell is thus
an open system.
Cell
Environment
2. Reproduction (growth)
Chemicals from the environment are turned into new cells under
the genetic direction of preexisting cells.
3. Differentiation
Some cells can form new cell structures such as a spore, usually
as part of a cellular life cycle.
Spore
4. Communication
Cells communicate or interact by means of chemicals that are
released or taken up.
5. Movement
Some cells are capable of self-propulsion.
6. Evolution
Cells contain genes and evolve to display new biological
properties. Phylogenetic trees show the evolutionary
relationships between cells.
Ancestral
cell
Distinct
species
Distinct
species
Fig. 1-3-1
1. Compartmentalization and metabolism
Cells take up nutrients from the environment, transform them,
and release wastes into the environment. The cell is thus
an open system.
Cell
Environment
2. Reproduction (growth)
Chemicals from the environment are turned into new cells under
the genetic direction of preexisting cells.
3. Differentiation
Some cells can form new cell structures such as a spore, usually
as part of a cellular life cycle.
Spore
Fig. 1-3-2
4. Communication
Cells communicate or interact by means of chemicals that are
released or taken up.
5. Movement
Some cells are capable of self-propulsion.
6. Evolution
Cells contain genes and evolve to display new biological
properties. Phylogenetic trees show the evolutionary
relationships between cells.
Ancestral
cell
Distinct
species
Distinct
species
Fig. 1-4
Coding
functions
Machine
functions
Energy conservation:
ATP
ADP + Pi
DNA
Replication
Gene expression
Transcription
Metabolism: generation
of precursors of macromolecules (sugars, amino
acids, fatty acids, etc.)
Enzymes: metabolic catalysts
RNA
Translation
Proteins
Reproduction (growth)
Diversity of Bacteria
• Come in various shapes, sizes, and colors
Fig. 4-1
Coccus
Rod
Spirillum
Spirochete
Hypha
Stalk
Budding and
appendaged bacteria
Filamentous bacteria
Rhodospirillum rubrum
Serra%a marcescens
Pseudomonas Aeruginosa
Diversity of Bacteria
• Come in various shapes, sizes, and colors
• Nutrient sources vary
• Growth condiEons vary
Bacteria are EVERYWHERE
• Soil, water, skin, mucosa, your intesEnes,
surfaces in public places, surfaces in your home,
etc.
• A single teaspoon of topsoil contains about a
billion bacterial cells
• Some bacteria can grow in the absence of oxygen
(anaerobic)
• Other bacteria can grow only in the presence of
oxygen (aerobic)
• Some can switch based on environmental
condiEons
Nutrient Sources
• Bacteria are not closed systems, they need
external input for nutriEon and growth
• Some bacteria are photosyntheEc (o[en
contain pigments to absorb light)
Nutrient Sources
• Bacteria are not closed systems, they need
external input for nutriEon and growth
• Some bacteria are photosyntheEc (o[en
contain pigments to absorb light)
Rhodobacter
Nutrient Sources
• Bacteria are not closed systems, they need
external input for nutriEon and growth
• Some bacteria are photosyntheEc (o[en
contain pigments to absorb light)
• Others use standard uptake/import of
environmental nutrients
Fig. 4-13
Lac permease
(a symporter)
Sodium–proton antiporter
Phosphate symporter
Potassium uniporter
Sulfate symporter
Out
In
Fig. 5-15
STAGE I: PREPARATORY
REACTIONS
Glucose
Hexokinase
Glucose-6-
Isomerase
Fructose-6-
Phosphofructokinase
Fructose-1,6Aldolase
STAGE II: MAKING ATP
AND PYRUVATE
Glyceraldehyde-3-
2
Glyceraldehyde-3-P
dehydrogenase
2
Electrons
1,3-Bisphosphoglycerate-
2
2 NAD+
2 NADH
To
Stage III
Phosphoglycerokinase
2 3-Phosphoglycerate-
2 2-PhosphoglycerateEnolase
2 Phosphoenolpyruvate-
STAGE III: MAKING
FERMENTATION
PRODUCTS
Pyruvate kinase
2 PyruvateNADH
To Stage II
NAD+
Lactate
Pyruvate
dehydrogenase decarboxylase
Pyruvate:Formate lyase
Acetate-+ formateLactate-
Acetaldehyde
Alcohol
dehydrogenase
Formate
hydrogenlyase
H2 + CO2
NADH
NAD+
Ethanol
CO2
To Stage II
Fig. 5-22a
Pyruvate- (three carbons)
Key
C2
C4
C5
C6
Acetyl-CoA
Oxalacetate2-
Citrate3Aconitate3-
Malate2Isocitrate3Fumarate2-
Succinate2-
α–Ketoglutarate2Succinyl-CoA
Fig. 5-20
E0ʹ′ (V)
–0.22
0.0
Complex II
Fumarate
Succinate
CYTOPLASM
+0.1
Comp
lex III
+0.36
+0.39
ENVIRONMENT
E0ʹ′ (V)
Diversity of Bacteria
• Come in various shapes, sizes, and colors
• Nutrient sources vary
• Growth condiEons vary
• ClassiﬁcaEons based on cell structure
Classes of Bacteria
• Referred to by their “Gram” classiﬁcaEon
• Gram negaEve (G-‐, Gram-‐) or Gram posiEve (G
+, Gram+)
– Based on ability to be stained with
• Major diﬀerence is the architecture of the cell
membrane/envelope
Fig. 4-16
Gram–negative
Gram–positive
Peptidoglycan
Peptidoglycan
Cytoplasm
Cytoplasm
Cytoplasmic membrane
Periplasm
Outer membrane
(Iipopolysaccharide and protein)
Membrane
Outer membrane
Peptidoglycan
Cytoplasmic
membrane
Cytoplasmic
membrane
Peptidoglycan
Fig. 4-18
N-Acetylglucosamine (G)
β(1,4
)
N-Acetylmuramic acid (M)
β(1,4
)
β(1,4
)
N-Acetyl
group
Peptide
cross-links
Lysozymesensitive
bond
L-Alanine
D-Glutamic acid
Meso-diaminopimelic acid
D-Alanine
Fig. 4-19
Glycan backbone
Interbridge
Peptides
Escherichia coli
(gram-negative)
Peptide bonds
Staphylococcus aureus
(gram-positive)
Glycosidic bonds
Fig. 4-20b
Wall-associated
protein
Teichoic acid
Lipoteichoic
acid
Peptidoglycan
Cytoplasmic
membrane
Fig. 4-21
Wall
Membrane
Lysozyme
digests wall
H2O enters
H2O enters
H2O enters
Low solute solution
Lysis
Lysozyme
digests wall
Protoplast
Isotonic solute solution
Fig. 4-22
O-specific polysaccharide
n
Core polysaccharide
Lipid A
Fig. 4-23
O–polysaccharide
Core
polysaccharide
Lipid A
Protein
Out
Lipopolysaccharide
(LPS)
Cell
wall
Outer
membrane
8 nm
Porin
Periplasm
Cytoplasmic
membrane
Peptidoglycan
Phospholipid
Lipoprotein
In
Fig. 4-24
Outer membrane
Periplasm
Cytoplasmic
membrane
Fig. 4-25
Lysozyme-insensitive
N-Acetyl
group
β(1,3)
N-Acetylglucosamine
Peptide
cross-links
N-Acetyltalosaminuronic acid
Part 3
Part 2
Part 1
Fig. 4-26
So then, how does a Gram stain work?
• Hans ChrisEan Gram developed this staining
protocol to disEnguish causaEve agents in
pneumonia
• There were 3 known causes for pneumonia:
– Bacterial – S. pneumoniae, gram negaEve
– Bacterial – K. pneumoniae, gram posiEve
– Viral – unknown agent in Gram’s Eme
• Gram stain can disEnguish between the bacterial
causaEve agents
• Allowed pneumonia paEents to be housed based
on the causaEve agent, prevenEng cross
infecEons
So then, how does a Gram stain work?
• Bacteria are ﬁrst stained with crystal
violet
• Gram POSITIVE bacteria retain the CV
(the CV binds to the pepEdoglycan
layer and is retained).
• A counterstain is added that binds all
bacteria (usually safranin) and colors
them red. Does NOT mask the CV
• A full procedure can be found here:
h>p://serc.carleton.edu/microbelife/
research_methods/microscopy/
gramstain.html
A Gram stain of mixed
Staphylococcus aureus (S.
aureus ATCC 25923, Gram-‐
posiEve cocci, in purple) and
Escherichia coli (E. coli ATCC
11775, gram-‐negaEve bacilli,
in pink-‐red)
References
•
•
•
•
•
•
•
•
•
•
•
h>p://cells-‐breannaolivia.weebly.com/prokaryotes-‐vs-‐eukaryotes.html
h>p://gookumpucky.blogspot.com/2011/01/serraEa-‐marcescens.html
h>ps://microbewiki.kenyon.edu/
h>p://www.chromagar.com/food-‐water-‐chromagar-‐pseudomonas-‐focus-‐
on-‐pseudomonas-‐36.html#.VP7tZeFm330
deadlymicrobes.com
www.tokresource.org
h>p://www.microbiologyonline.org.uk/about-‐microbiology/introducing-‐
microbes/overview
www.ks.uiuc.edu
h>p://www.psi.ch/swissfel/the-‐photocycle-‐of-‐bacteriorhodopsin
Wikimedia
Brock – microbiology of Microogranisms 12th ed
Resistance
caputo@rowan.edu
The World Health Organiza:on warns that
An:bio:c resistance is a “Global Threat”
The chief medical oﬃcer for England, Prof
Dame Sally Davies, said the rise in drug-‐
resistant infec:ons
was comparable to the threat of global
warming.
Deﬁni:ons
• An#bio#c resistance
drug resistance
whereby some sub-‐
popula:on of a
bacterial species is able
to survive aLer
exposure to one or
more an:bio:cs
• Mul#drug resistance
(MDR) -‐ pathogens
resistant to mul:ple
an:bio:cs
Mechanisms of Resistance
Four main categories
i) restricted access to target/
restricted accumula:on to
inhibitory concentra:on
ii) inac:va:on/destruc:on of
an:bio:c
iii) modiﬁca:on of target
iv) failure to ac:vate an:bio:c
Limi:ng access to an:bio:c
• Polarity of an:microbial drugs
determine the diﬀusion/
passage across the membrane

• Outer Membrane Porins
– Beta-‐barrel proteins in the OM
– reduce number of porins in the
outer membrane which
decreases ﬂux of molecules
across the outer membrane (G-‐)
OmpF
• OmpF is an E.coli
general diﬀusion
porin.
• Central pore
through the core
of the β-‐barrel
Modiﬁca:on of Entry Mechanisms
Eﬄux Pumps
• Used to pump
compounds OUT of
cells
• Energy dependent
process
– Primary
– Secondary
RND Eﬄux pumps
Enzyma:c Inac:va:on of An:bio:c
• Enzymes that break down an:bio:cs
• Usually modify the an:bio:c at sites involved in mechanism of
an:bio:cs
• Well characterized example: Beta-‐lactamases
– cleave beta-‐lactam ring
– Secreted into periplasm of G –
– Speciﬁc to beta lactam an:bio:cs
Modiﬁca:on of Drug Target
• Accumula:on of
spontaneous
muta:ons
• Reduc:on of aﬃnity
for target
• Modiﬁca:on of ac:ve
site / binding site
residues
Prokaryotes grow on surfaces as bioﬁlms
•
Microorganisms a`ach to surfaces and
develop bioﬁlms.
•
Bioﬁlms may form on a wide variety of
surfaces, including living :ssues, indwelling
medical devices, industrial or potable water
system piping, or natural aqua:c systems.
Can contain mul:ple species of bacteria
Bioﬁlm-‐associated cells can be diﬀeren:ated
from their suspended counterparts by
•
•
– genera:on of an extracellular polymeric
substance (EPS) matrix,
– reduced growth rates,
– up-‐ and down-‐regula:on of speciﬁc
genes.
Bioﬁlm forma:on
• Adhesion to surfaces begins the process
• Genes are ac:vated promo:ng sedentary
growth and EPS secre:on
• Individual bacterial colonies can be separated
from one another in the ﬁlm
• Some bacteria can be triggered into bioﬁlm
forma:on aLer exposure to an:bio:cs
Polymicrobic bioﬁlm grown on a stainless steel surface in a laboratory potable water
bioﬁlm reactor for 14 days, then stained with 4,6-‐diamidino-‐2-‐phenylindole (DAPI) and
examined by epiﬂuorescence microscopy. Bar, 20 m.
Growth on Medical devices
Killing Bioﬁlms
• Added complexity
• EPS serves as a permeability barrier
• Mul:ple bacteria can be in the ﬁlm
complica:ng treatment
• Diﬀeren:al gene expression can impact
eﬃcacy
References
• Wikipedia
• h`p://www.wiley.com/college/pra`/0471393878/instructor/
ac:vi:es/bacterial_drug_resistance/index.html
• Brock Microbiology
• h`p://www.ncbi.nlm.nih.gov/pmc/ar:cles/PMC2696358/
• doi: 10.1128/CMR.00043-‐12
• pharmaceu:calintelligence.com
• h`p://journals.sfu.ca/rncsb/index.php/csbj/ar:cle/view/csbj.
201302008/228
• h`p://www.nature.com/nrmicro/journal/v13/n1/full/
nrmicro3380.html
• Cdc.gov
• h`p://www.usmed-‐online.de/usmed/index.php/de/citra-‐lock/
informa:onen?showall=1&limitstart=
An#bio#cs

Lark J. Perez

An#bio#c Classes by Mechanism of Ac#on and History
An#bio#cs – Classes and Historical Perspec#ve
An#bio#cs – Classes and Historical Perspec#ve
An#bio#cs – Classes and Historical Perspec#ve
An#bio#cs – Classes and Historical Perspec#ve
An#bio#cs – Increasing Demand BUT Empty Supply
DEMAND
SUPPLY
1983-‐
1987
1988-‐
1992
1993-‐
1997
1998-‐
2002
2003-‐
2007
2008-‐
2011
An#bio#cs – Increasing Demand…WHY?
DEMAND
An#bio#cs – Increasing Demand…WHY?
DEMAND
An#bio#cs – Increasing Demand…WHY?
DEMAND
Bacteria adapt resistance to an#bio#cs
in many ways…
-‐changed an2bio2c targets
-‐an2bio2c degrading or altering enzymes
-‐drug eﬄux pumps
An#bio#cs – Increasing Demand…WHY?
DEMAND
Bacteria adapt resistance to an#bio#cs
in many ways…
-‐changed an2bio2c targets
-‐an2bio2c degrading or altering enzymes
-‐drug eﬄux pumps
…and, they rapidly share these new
adapta#ons with other bacteria.
An#bio#cs – Increasing Demand…WHY?
DEMAND
Bacteria adapt resistance to an#bio#cs
in many ways…
-‐changed an2bio2c targets
-‐an2bio2c degrading or altering enzymes
-‐drug eﬄux pumps
…and, they rapidly share these new
adapta#ons with other bacteria.
An#bio#cs – Increasing Demand…WHY?
DEMAND
Bacteria adapt resistance to an#bio#cs
in many ways…
-‐changed an2bio2c targets
-‐an2bio2c degrading or altering enzymes
-‐drug eﬄux pumps
…and, they rapidly share these new
adapta#ons with other bacteria.
An#bio#cs – Increasing Demand…WHY?
DEMAND
Bacteria adapt resistance to an#bio#cs
in many ways…
-‐changed an2bio2c targets
-‐an2bio2c degrading or altering enzymes
-‐drug eﬄux pumps
…and, they rapidly share these new
adapta#ons with other bacteria.
An#bio#cs – Increasing Demand…WHY?
DEMAND
Bacteria adapt resistance to an#bio#cs
in many ways…
-‐changed an2bio2c targets
-‐an2bio2c degrading or altering enzymes
-‐drug eﬄux pumps
…and, they rapidly share these new
adapta#ons with other bacteria.
An#bio#cs – Decreasing Supply…WHY?
SUPPLY
1983-‐
1987
1988-‐
1992
1993-‐
1997
1998-‐
2002
2003-‐
2007
2008-‐
2011
No single reason, many contribu#ng
factors, including:
-‐ exis2ng an2bio2cs fail largely due to
misuse and misprescrip2on
-‐ ﬁnancial considera2ons…expensive
to develop (like any drug) and used
for possibly 1-‐week per year (not a
chronic illness in most cases) coupled
to “guaranteed” misuse and
resistance
-‐ all “easy” molecular targets and
drug classes have been developed.
An#bio#cs – Increasing Demand BUT Empty Supply…WHAT HAPPENS?
Two U.S. presiden2al sons.
Calvin Coolidge Jr.
Franklin Delano Roosevelt Jr.
An#bio#cs – Increasing Demand BUT Empty Supply…WHAT HAPPENS?
Two U.S. presiden2al sons.
Calvin Coolidge Jr.
Franklin Delano Roosevelt Jr.
Age 16 – developed bacterial infec2on
from a blister received during a tennis
match, died 8 days later.
Age 22 – developed severe bacterial
throat infec2on, complete recovery
a[er receiving the ﬁrst an2bio2c.
New York Times, July 8th, 1924
Medicine: Prontosil, TIME
Magazine, December 28th, 1936
An#bio#cs – Increasing Demand BUT Empty Supply…WHAT HAPPENS?
Two U.S. presiden2al sons.
Calvin Coolidge Jr.
Franklin Delano Roosevelt Jr.
Age 16 – developed bacterial infec2on
from a blister received during a tennis
match, died 8 days later.
Age 22 – developed severe bacterial
throat infec2on, complete recovery
a[er receiving the ﬁrst an2bio2c.
New York Times, July 8th, 1924
Medicine: Prontosil, TIME
Magazine, December 28th, 1936
An#bio#cs – Increasing Demand BUT Empty Supply…WHAT HAPPENS?
-‐ Elec2ve surgery becomes a very serious business with a high risk of mortality from
some complica2ng infec2on.
-‐ Forget organ transplants, immune suppression would almost certainly be fatal in these
pa2ents.
-‐ HIV and other diseases and treatments eﬀec2ng the immune system would be
signiﬁcantly more dangerous.
-‐ Re2rements would quickly get shorter. Before an2bio2cs, the average 60 year old who
caught pneumonia was more likely than not to die of it than not.
-‐ Maternal mortality would be a lot higher.
-‐ Neonates would be much more likely to succumb to infec2on, having underdeveloped
immune systems.
-‐ Chronic, untreated bacterial infec2ons can lead to various types of cancer (e.g.
stomach cancer) and other diseases which would increase in occurrence.
-‐ The severely disabled would have much shorter life spans. Without an2bio2cs, there
would be no way to treat the bed sores, or the lung and urinary tract infec2ons that
are common for people with limited sensa2on or mobility.
Take Home: An#bio#cs are important to human health.
An#bio#cs

Lark J. Perez

Introduc#on to An#bio#c Classes by Mechanism of Ac#on
An#bio#cs History and Major Classes – Preface
Paul Ehrlich (Nobel Prize 1908)
‘It will, in short, become possible to introduce into the economy a molecular
mechanism which, like a very cunningly contrived torpedo, shall ﬁnd its way to some
parAcular group of living elements, and cause an explosion among them, leaving the
rest untouched.’

-‐T. Huxley (1881)
An#bio#cs History and Major Classes – Preface
An#bio#cs – Classes and Historical Perspec#ve
An#bio#cs History and Major Classes – Sulfonamide Drugs
Gerhard Domangk (Nobel Prize 1939)
An#bio#cs History and Major Classes – Sulfonamide Drugs
O O
S
H 2N
Gerhard Domangk (Nobel Prize 1939)
O O
-‐ Discovered
S by
NH 2
screening Ncompound
N
N
libraries for ac2vity.
NH 2
prontosil
-‐ First sulfonamide
eﬀec2ve drug
against
infec2ous
functional
group
diseases.

Key feature in
antibiotic
“sulfahis
-‐ Domangk
saved
drug”
class.
O O
daughter from
S
H 2N
Antibiotics
this
having
her ﬁinnger
class universally
NH 2
amputated.
inhibit DNA
sulfanilamide
synthesis.
‘The least hint that a substance might be eﬀecAve was recorded and followed up by the
chemists who, on the strength of it, made innumerable syntheses.’

-‐G. Domangk (1939)
An#bio#cs History and Major Classes – Sulfonamide Drugs
O O
S
H 2N
O O
S
N
NH 2
N
N
NH 2
prontosil
sulfonamide
functional
group
Key feature in
antibiotic “sulfa
drug” class.
O O
S
H 2N
NH 2
sulfanilamide
Antibiotics in this
class universally
inhibit DNA
synthesis.
An#bio#cs – Classes and Historical Perspec#ve
An#bio#cs History and Major Classes – β-‐Lactam Drugs
hgps://www.youtube.com/watch?
v=5RGs-‐2eNnjM&list=PLAPp-‐
HtsJec5hORrThORgZ3-‐bk9gHyBLy&index=20
An#bio#cs History and Major Classes – β-‐Lactam Drugs
Sir Alexander Fleming (Nobel
Prize 1948)
‘One someAmes ﬁnds what one is not
looking for.’

-‐ A. Fleming
An#bio#cs History and Major Classes – β-‐Lactam Drugs
An#bio#cs History and Major Classes – β-‐Lactam Drugs
An#bio#cs History and Major Classes – β-‐Lactam Drugs
An#bio#cs History and Major Classes – β-‐Lactam Drugs
An#bio#cs History and Major Classes – β-‐Lactam Drugs
“This delicate process has more hazards than an obstacle race. The
penicillium mold, found in fer#le soil, is cul#vated in a sugary solu#on. It
develops a network of very ﬁne branches, called “mycelium,” which
secrete penicillin. If the delicate mycelium breaks, produc#on of
penicillin stops. Temperature must be kept at 24°C. Worst of all hazards
is contamina#on. The sugary bath in which the mold grows is an ideal
medium for bacteria; if any get in, they destroy all penicillin present in
three hours. And when all these hazards are survived, the yield is
fantas#cally small. The broth from which powdered penicillin is
extracted contains only two to six thousandths of 1% of pure penicillin.”

See more at:
h]p://scopeblog.stanford.edu/2010/09/26/
image_of_the_week_penicillin/#sthash.AYt3WjBV.dpuf
An#bio#cs History and Major Classes – β-‐Lactam Drugs
Structures
Proposed
for Pennicillins:
H
N
O
R
O
S
O
N
N
H
R
CO2H
O
R
S
N
H
N
O
N
O
HO 2C
S
O
In the ini2al “SECRET” report (Oct 22, 1943), “…one of us [R. Robinson] considers the four-‐ring structure
somewhat improbable.” See J. Chem. Educ. 2004, 81 (10), 1462 for more informa2on.
For addi2onal reading on the history
of penicillin, see:
hgp://www.acs.org/content/acs/en/
educa2on/wha2schemistry/landmarks/
ﬂemingpenicillin.html
An#bio#cs History and Major Classes – β-‐Lactam Drugs
‘ At the Ame of my successful
synthesis of Penicillin V in 1957, I
compared the problem of trying to
synthesize penicillin by classical
methods to that of aZempAng to
repair the mainspring of a ﬁne
watch with a blacksmiths anvil,
hammer and tongs.’

-‐J. Sheehan (1982)
An#bio#cs History and Major Classes – β-‐Lactam Drugs
R.B. Woodward (Nobel Prize 1965)
O
HO
H
N
O
H 2N
S
N
OAc
O
O
OH
‘Again, the very existence of this substance, containing as it does potenAaliAes for
annihilaAon parallel to those discussed above in some detail, further compounded
by the considerable strain within the β-‐lactam ring, represents a major result of our
invesAgaAon.’

-‐R.B. Woodward (1965)
An#bio#cs History and Major Classes – β-‐Lactam Drugs
β-lactam antibiotics
NH 2
N
O
O
β-‐lactam
func#onal
group

Key feature in
β-‐lactam an#bio#c
class.

An#bio#cs in this
class universally
inhibit cell wall
synthesis.
H H H
N
S
N
O
S
N
O
O
OH
Imipenem
Penicillin Class (Penams)
Carbapenam Class
N
H 2N
NH
Ampicillin
H 3C
H 3C
S
CH 3
CH 3
OH
O
HN
OH
H H
N
O
OH
H 3C
H 3C
H H H
N
S
N
O
O
N
N
S
O
O
O
H 2N
N
O
OH
O
H
N
O
CH 3
N
O
SO 3H
Ceftazidime
Aztreonam
Cephalosporin Class (Cephems)
Monobactam Class
An#bio#cs History and Major Classes – β-‐Lactam Drugs
NH 2
N
O
O
β-‐lactam
func#onal
group

Key feature in
β-‐lactam an#bio#c
class.

An#bio#cs in this
class universally
inhibit cell wall
synthesis.
H H H
N
S
N
O
S
N
O
O
OH
Imipenem
Penicillin Class (Penams)
Carbapenam Class
N
H 2N
NH
Ampicillin
H 3C
H 3C
S
CH 3
CH 3
OH
O
HN
OH
H H
N
O
OH
H 3C
H 3C
H H H
N
S
N
O
O
N
N
S
O
O
O
H 2N
N
O
OH
O
H
N
O
CH 3
N
O
SO 3H
Ceftazidime
Aztreonam
Cephalosporin Class (Cephems)
Monobactam Class
An#bio#cs History and Major Classes – β-‐Lactam Drugs
NH 2
N
O
O
β-‐lactam
func#onal
group

Key feature in
β-‐lactam an#bio#c
class.

An#bio#cs in this
class universally
inhibit cell wall
synthesis.
H H H
N
S
N
O
S
N
O
O
OH
Imipenem
Penicillin Class (Penams)
Carbapenam Class
N
H 2N
NH
Ampicillin
H 3C
H 3C
S
CH 3
CH 3
OH
O
HN
OH
H H
N
O
OH
H 3C
H 3C
H H H
N
S
N
O
O
N
N
S
O
O
O
H 2N
N
O
OH
O
H
N
O
CH 3
N
O
SO 3H
Ceftazidime
Aztreonam
Cephalosporin Class (Cephems)
Monobactam Class
An#bio#cs – Classes and Historical Perspec#ve
An#bio#cs History and Major Classes – Streptomycin
hgps://www.youtube.com/watch?v=aiXoguk-‐
FUI&list=PLAPp-‐HtsJec5hORrThORgZ3-‐
bk9gHyBLy&index=16
An#bio#cs History and Major Classes – Streptomycin
Selman Waksman (right, Nobel Prize 1952)
and Albert Schatz (le[) isolate streptomycin
from the ac2nobacterium Streptomyces griseus.
An#bio#cs History and Major Classes – Streptomycin
Selman Waksman (right, Nobel Prize 1952)
and Albert Schatz (le[) isolate streptomycin
from the ac2nobacterium Streptomyces griseus.
Streptomycin displays potent ac2vity against
Mycobacterium tuberculosis.
Chemotherapy, including streptomycin
contributes to rapid drop in TB deaths.
An#bio#cs History and Major Classes – Streptomycin
Selman Waksman (right, Nobel Prize 1952)
and Albert Schatz (le[) isolate streptomycin
from the ac2nobacterium Streptomyces griseus.
Streptomycin displays potent ac2vity against
Mycobacterium tuberculosis.
Chemotherapy, including streptomycin
contributes to rapid drop in TB deaths.
Currently, one person dies from TB
every 20 seconds.
An#bio#cs History and Major Classes – Streptomycin and
Tetracycline
O
HO
HO
HO
H CH 3
HO
O
O HO
O
H
HN CH 3
O
H
OH O
OH
OH O
OH
O
NH 2
N
N
NH 2
H
H 3C OH
OH NH 2
NH 2
H
H 3C
OH
N
CH 3
H 2N
OH
Streptomycin
R 2N
NR 2
Tetracycline
First, representative
member of the
aminoglycoside
class of antibiotics.
RO
OR
Parent member of
the tetracycline
class of antibiotics.
Antibiotics in this
class universally
inhibit protein
synthesis by binding
the 30S subunit of
the ribosome.
OR
Many members
of the aminoglycoside
class of antibiotics
(excluing streptomycin)
contain a 2deoxystreptamine
motif.
Antibiotics in this
class universally
inhibit protein
synthesis by binding
the 30S subunit of
the ribosome.
O
OH O
O
NH 2
OH
H 3C OH
H 3C
N
CH 3
Until recently all
tetracycline antibiotics
were derived from
natural tetracyclines,
therefore the molecules
in this class are highly
similar in structure.
An#bio#cs History and Major Classes – Streptomycin and
Tetracycline
O
HO
HO
HO
H CH 3
HO
O
O HO
O
H
HN CH 3
O
H
OH O
OH
OH O
OH
O
NH 2
N
N
NH 2
H
H 3C OH
OH NH 2
NH 2
H
H 3C
OH
N
CH 3
H 2N
OH
Streptomycin
R 2N
NR 2
Tetracycline
First, representative
member of the
aminoglycoside
class of antibiotics.
RO
OR
Parent member of
the tetracycline
class of antibiotics.
Antibiotics in this
class universally
inhibit protein
synthesis by binding
the 30S subunit of
the ribosome.
OR
Many members
of the aminoglycoside
class of antibiotics
(excluing streptomycin)
contain a 2deoxystreptamine
motif.
Antibiotics in this
class universally
inhibit protein
synthesis by binding
the 30S subunit of
the ribosome.
O
OH O
O
NH 2
OH
H 3C OH
H 3C
N
CH 3
Until recently all
tetracycline antibiotics
were derived from
natural tetracyclines,
therefore the molecules
in this class are highly
similar in structure.
An#bio#cs History and Major Classes – Streptomycin and
Tetracycline
O
HO
HO
HO
H CH 3
HO
O
O HO
O
H
HN CH 3
O
H
OH O
OH
OH O
OH
O
NH 2
N
N
NH 2
H
H 3C OH
OH NH 2
NH 2
H
H 3C
OH
N
CH 3
H 2N
OH
Streptomycin
R 2N
NR 2
Tetracycline
First, representative
member of the
aminoglycoside
class of antibiotics.
RO
OR
Parent member of
the tetracycline
class of antibiotics.
Antibiotics in this
class universally
inhibit protein
synthesis by binding
the 30S subunit of
the ribosome.
OR
Many members
of the aminoglycoside
class of antibiotics
(excluing streptomycin)
contain a 2deoxystreptamine
motif.
Antibiotics in this
class universally
inhibit protein
synthesis by binding
the 30S subunit of
the ribosome.
O
OH O
O
NH 2
OH
H 3C OH
H 3C
N
CH 3
Until recently all
tetracycline antibiotics
were derived from
natural tetracyclines,
therefore the molecules
in this class are highly
similar in structure.
An#bio#cs History and Major Classes – Streptomycin and
Tetracycline
O
HO
HO
HO
H CH 3
HO
O
O HO
O
H
HN CH 3
O
H
OH O
OH
OH O
OH
O
NH 2
N
N
NH 2
H
H 3C OH
OH NH 2
NH 2
H
H 3C
OH
N
CH 3
H 2N
OH
Streptomycin
R 2N
NR 2
Tetracycline
First, representative
member of the
aminoglycoside
class of antibiotics.
RO
OR
Parent member of
the tetracycline
class of antibiotics.
Antibiotics in this
class universally
inhibit protein
synthesis by binding
the 30S subunit of
the ribosome.
OR
Many members
of the aminoglycoside
class of antibiotics
(excluing streptomycin)
contain a 2deoxystreptamine
motif.
Antibiotics in this
class universally
inhibit protein
synthesis by binding
the 30S subunit of
the ribosome.
O
OH O
O
NH 2
OH
H 3C OH
H 3C
N
CH 3
Until recently all
tetracycline antibiotics
were derived from
natural tetracyclines,
therefore the molecules
in this class are highly
similar in structure.
An#bio#cs – Classes and Historical Perspec#ve
An#bio#cs History and Major Classes – Macrolides and
Chloramphenicol
O
H 3C
HO
H 3C
H 3C
CH 3
OH
H 3C
O
O
OH
CH 3
HO
O
O
CH 3
O
OH OH
N(CH 3)2
O
OCH3
OH
OH
CH 3
Erythromycin
Representative
member of the
macrolide class of
antibiotics.
Antibiotics in this
class universally
inhibit protein
synthesis by binding
the 50S subunit of
the ribosome.
Cl
CH 3
O2N
O
H 3C
HO
H 3C
H 3C
O
OR
CH 3
HO
O
O
CH 3
O
Cl
O
CH 3
OH
H 3C
O
HN
N(CH 3)2
O
CH 3
OCH3
OH
OH
CH 3
Macrolide antibiotics
are derived from
natural macrolides,
therefore the molecules
in this class are highly
similar in structure, only
differing at the ketone
and 7-hydroxy substituent.
Chloramphenicol
No other derivatives
of this compound
are used as
antibiotics.
Chloramphenicol
inhibits protein
synthesis by binding
the 50S subunit of
the ribosome.
An#bio#cs History and Major Classes – Macrolides and
Chloramphenicol
O
H 3C
HO
H 3C
H 3C
CH 3
OH
H 3C
O
O
OH
CH 3
HO
O
O
CH 3
O
OH OH
N(CH 3)2
O
OCH3
OH
OH
CH 3
Erythromycin
Representative
member of the
macrolide class of
antibiotics.
Antibiotics in this
class universally
inhibit protein
synthesis by binding
the 50S subunit of
the ribosome.
Cl
CH 3
O2N
O
H 3C
HO
H 3C
H 3C
O
OR
CH 3
HO
O
O
CH 3
O
Cl
O
CH 3
OH
H 3C
O
HN
N(CH 3)2
O
CH 3
OCH3
OH
OH
CH 3
Macrolide antibiotics
are derived from
natural macrolides,
therefore the molecules
in this class are highly
similar in structure, only
differing at the ketone
and 7-hydroxy substituent.
Chloramphenicol
No other derivatives
of this compound
are used as
antibiotics.
Chloramphenicol
inhibits protein
synthesis by binding
the 50S subunit of
the ribosome.
An#bio#cs History and Major Classes – Macrolides and
Chloramphenicol
O
H 3C
HO
H 3C
H 3C
CH 3
OH
H 3C
O
O
OH
CH 3
HO
O
O
CH 3
O
OH OH
N(CH 3)2
O
OCH3
OH
OH
CH 3
Erythromycin
Representative
member of the
macrolide class of
antibiotics.
Antibiotics in this
class universally
inhibit protein
synthesis by binding
the 50S subunit of
the ribosome.
Cl
CH 3
O2N
O
H 3C
HO
H 3C
H 3C
O
OR
CH 3
HO
O
O
CH 3
O
Cl
O
CH 3
OH
H 3C
O
HN
N(CH 3)2
O
CH 3
OCH3
OH
OH
CH 3
Macrolide antibiotics
are derived from
natural macrolides,
therefore the molecules
in this class are highly
similar in structure, only
differing at the ketone
and 7-hydroxy substituent.
Chloramphenicol
No other derivatives
of this compound
are used as
antibiotics.
Chloramphenicol
inhibits protein
synthesis by binding
the 50S subunit of
the ribosome.
An#bio#cs – Classes and Historical Perspec#ve
An#bio#cs History and Major Classes – Rifamycin and
Quinolones
CH 3 CH 3
HO
H 3C
OH O
AcO
OH OH
H 3C CH 3
NH
H 3CO
O
O
O
O
H 3C
O
O
CH 3
Antibiotics in this
class universally
inhibit RNA
synthesis by binding
RNA polymerase.
F
HO
N
CH 3 CH 3
HO
H
3C
OH
OH O
AcO
OH OH
H 3C CH 3
NH
H 3CO
O
O
O
O
O
F
HO
CH 3
N
Ciprofloxacin
O
O
H 3C
N
NH
Rifamycin B
Parent member of
the rifamycin class
of antibiotics.
O
OH
Rifamycin antibiotics
are derived from
natural rifamycins,
therefore the molecules
in this class are highly
similar in structure.
Representative
member of the
quinolone
(fluoroquinolone)
class of antibiotics.
Antibiotics in this
class universally
inhibit DNA
topoisomerase.
Quinolone
antibiotics are fully
synthetic. The
fluorine (shown) is
not necessary but
is present in many
members of this
class. Antibiotics
with this fluorine
are called
fluoroquinolones.
An#bio#cs History and Major Classes – Rifamycin and
Quinolones
CH 3 CH 3
HO
H 3C
OH O
AcO
OH OH
H 3C CH 3
NH
H 3CO
O
O
O
O
H 3C
O
O
CH 3
Antibiotics in this
class universally
inhibit RNA
synthesis by binding
RNA polymerase.
F
HO
N
CH 3 CH 3
HO
H
3C
OH
OH O
AcO
OH OH
H 3C CH 3
NH
H 3CO
O
O
O
O
O
F
HO
CH 3
N
Ciprofloxacin
O
O
H 3C
N
NH
Rifamycin B
Parent member of
the rifamycin class
of antibiotics.
O
OH
Rifamycin antibiotics
are derived from
natural rifamycins,
therefore the molecules
in this class are highly
similar in structure.
Representative
member of the
quinolone
(fluoroquinolone)
class of antibiotics.
Antibiotics in this
class universally
inhibit DNA
topoisomerase.
Quinolone
antibiotics are fully
synthetic. The
fluorine (shown) is
not necessary but
is present in many
members of this
class. Antibiotics
with this fluorine
are called
fluoroquinolones.
An#bio#cs History and Major Classes – Rifamycin and
Quinolones
CH 3 CH 3
HO
H 3C
OH O
AcO
OH OH
H 3C CH 3
NH
H 3CO
O
O
O
O
H 3C
O
O
CH 3
Antibiotics in this
class universally
inhibit RNA
synthesis by binding
RNA polymerase.
F
HO
N
CH 3 CH 3
HO
H
3C
OH
OH O
AcO
OH OH
H 3C CH 3
NH
H 3CO
O
O
O
O
O
F
HO
CH 3
N
Ciprofloxacin
O
O
H 3C
N
NH
Rifamycin B
Parent member of
the rifamycin class
of antibiotics.
O
OH
Rifamycin antibiotics
are derived from
natural rifamycins,
therefore the molecules
in this class are highly
similar in structure.
Representative
member of the
quinolone
(fluoroquinolone)
class of antibiotics.
Antibiotics in this
class universally
inhibit DNA
topoisomerase.
Quinolone
antibiotics are fully
synthetic. The
fluorine (shown) is
not necessary but
is present in many
members of this
class. Antibiotics
with this fluorine
are called
fluoroquinolones.
An#bio#cs History and Major Classes – Rifamycin and
Quinolones
CH 3 CH 3
HO
H 3C
OH O
AcO
OH OH
H 3C CH 3
NH
H 3CO
O
O
O
O
H 3C
O
O
CH 3
Antibiotics in this
class universally
inhibit RNA
synthesis by binding
RNA polymerase.
F
HO
N
CH 3 CH 3
HO
H
3C
OH
OH O
AcO
OH OH
H 3C CH 3
NH
H 3CO
O
O
O
O
O
F
HO
CH 3
N
Ciprofloxacin
O
O
H 3C
N
NH
Rifamycin B
Parent member of
the rifamycin class
of antibiotics.
O
OH
Rifamycin antibiotics
are derived from
natural rifamycins,
therefore the molecules
in this class are highly
similar in structure.
Representative
member of the
quinolone
(fluoroquinolone)
class of antibiotics.
Antibiotics in this
class universally
inhibit DNA
topoisomerase.
Quinolone
antibiotics are fully
synthetic. The
fluorine (shown) is
not necessary but
is present in many
members of this
class. Antibiotics
with this fluorine
are called
fluoroquinolones.
An#bio#cs – Overview of Upcoming Detailed Discussions
An#bio#cs

Lark J. Perez

β-‐lactam an#bio#cs and vancomycin
An#bio#cs – Classiﬁca#on by Mechanism of Ac#on
An#bio#cs – Classiﬁca#on by Mechanism of Ac#on
β-‐Lactam An#bio#cs -‐ Review
NH 2
N
O
O
β-‐lactam
func#onal
group

Key feature in
β-‐lactam an#bio#c
class.

An#bio#cs in this
class universally
inhibit cell wall
synthesis.
H H H
N
S
N
O
S
N
O
O
OH
Imipenem
Penicillin Class (Penams)
Carbapenam Class
N
H 2N
NH
Ampicillin
H 3C
H 3C
S
CH 3
CH 3
OH
O
HN
OH
H H
N
O
OH
H 3C
H 3C
H H H
N
S
N
O
O
N
N
S
O
O
O
H 2N
N
O
OH
O
H
N
O
CH 3
N
O
SO 3H
Ceftazidime
Aztreonam
Cephalosporin Class (Cephems)
Monobactam Class
β-‐Lactam An#bio#cs -‐ Overview
YouTube: h,ps://www.youtube.com/watch?v=qBdYnRhdWcQ
Bacterial Cell Wall Structure and Biosynthesis
Porin
Trends in Biotechnology 2010 28, 10, 596-‐604.
Bacterial Cell Wall Structure and Biosynthesis
Porin
carbohydrate
(-‐glycan)
pepLde
(pep#do-‐)
Trends in Biotechnology 2010 28, 10, 596-‐604.
Bacterial Cell Wall Structure and Biosynthesis
Porin
carbohydrate
(-‐glycan)
pepLde
(pep#do-‐)
Trends in Biotechnology 2010 28, 10, 596-‐604.
Bacterial Cell Wall Structure and Biosynthesis
NAM
Porin
NAG
carbohydrate
(-‐glycan)
pepLde
(pep#do-‐)
Trends in Biotechnology 2010 28, 10, 596-‐604.
Bacterial Cell Wall Structure and Biosynthesis
Porin
Vancomycin
carbohydrate
(-‐glycan)
pepLde
(pep#do-‐)
Trends in Biotechnology 2010 28, 10, 596-‐604.
Bacterial Cell Wall Structure and Biosynthesis
Porin
Vancomycin
β-‐Lactams
carbohydrate
(-‐glycan)
pepLde
(pep#do-‐)
Trends in Biotechnology 2010 28, 10, 596-‐604.
Peptide
H2N
H NH
H2N
H NH
O
The Final Step in Cell Wall Biosynthesis
O
O
HN
HN
(Gly)3 NH2 H
(Gly) 3 NH 2
( )4
H
( )4
O
HN
O
HN
H NH
O
H NH
O
H3C
H3C
O
O
β-‐Lactams HN H
HN H
CO2H
CO2H
H3C
H3 C
O
N-acetylglucosamine N-acetylmuramic acid
(NAG) OH
(NAM)
NHAc
O HO
O
O
O
O
O
NHAc
H3C
OH
O
HN H
O
CH
3
Peptide
H NH
H2N
O
O
HN
(Gly)3 NH2
( )4
H
O
HN
H NH
O
H3C
O
HN H
CO2H
H3C
Peptide
H2N
H NH
H2N
H NH
O
The Final Step in Cell Wall Biosynthesis
O
O
HN
HN
(Gly)3 NH2 H
(Gly) 3 NH 2
( )4
H
( )4
O
HN
O
HN
H NH
O
H NH
O
H3C
H3C
O
O
β-‐Lactams HN H
HN H
CO2H
CO2H
H3C
H3 C
O
N-acetylglucosamine N-acetylmuramic acid
(NAG) OH
(NAM)
NHAc
O HO
O
O
O
O
O
NHAc
H3C
OH
O
HN H
O
CH
3
Peptide
H NH
H2N
O
O
HN
(Gly)3 NH2
( )4
H
O
HN
H NH
O
H3C
O
HN H
CO2H
H3C
GlycosylaLon
(Vancomycin
inhibits this process)
The Final Step in Cell Wall Biosynthesis
β-‐Lactams
N-acetylglucosamine N-acetylmuramic acid
(NAG) OH
(NAM)
OH
NHAc
NHAc
O HO
O HO
O
O
O
O
O
O
O
O
O
NHAc
NHAc
H3C
H3 C
OH
OH
O
O
HN H
HN H
O
O
CH3
CH 3
H2N
Peptide H NH
H NH
H2N
O
O
O
O
HN
HN
(Gly)3 NH2 H
(Gly) 3 NH 2
( )4
H
( )4
O
HN
O
HN
H NH
O
H NH
O
H3C
H3C
O
O
HN H
HN H
CO2H
CO2H
H3C
H3 C
TranspepLdase (penicillin binding protein)
catalyzes crosslinking of pepLdoglycan
The Final Step in Cell Wall Biosynthesis
β-‐Lactams
D -Alanyl-D -alanine
N-acetylglucosamine N-acetylmuramic acid
(NAG) OH
(NAM)
OH
NHAc
NHAc
O HO
O HO
O
O
O
O
O
O
O
O
O
NHAc
NHAc
H3C
H3 C
OH
OH
O
O
HN H
HN H
O
O
CH3
CH 3
H2N
Peptide H NH
H NH
H2N
O
O
O
O
HN
HN
(Gly)3 NH2 H
(Gly) 3 NH 2
( )4
H
( )4
O
HN
O
HN
H NH
O
H NH
O
H3C
H3C
O
O
HN H
HN H
CO2H
CO2H
H3C
H3 C
H
ENZYME
H CH 3 O
N
Peptide
H CH 3
N
O
O
H CO2H
CH 3
H 2N
H CO2H
activated for nucleophilic
attack (peptidoglycan crosslinking)
H CH 3
N
Peptide
O
O
ENZYME
O
TranspepLdase (penicillin binding protein)
catalyzes crosslinking of pepLdoglycan
β-‐Lactam An#bio#cs – Mechanism of Ac#on
D -Alanyl-D -alanine
H
ENZYME
H CH 3 O
N
Peptide
H CH 3
N
O
O
H CO2H
β-lactam antibiotics (penicillins)
are active site mimics
H
ENZYME
H H H O
CH
S CH
N3
RH
3
N
Peptide
O H CH
N 3
CH 3
N
O
O
H CO2H
O
H CO2H
D -Alanyl-D -alanine
(natural substrate)
activated for nucleophilic
attack (peptidoglycan crosslinking)
H CH 3
N
Peptide
O
O
O
ENZYME
irreversible enzyme inhibition
R
H H H
O S O
N
ENZYME
H CH 3
H
OR
CH
S 3 CH
NN
3
O
CO2H CH 3
H HN
O
Penicillins
H CO2H
(substrate mimic)
TRANSPEPTIDASE (PENICILLIN BINDING PROTEIN)
β-‐Lactam An#bio#cs – Mechanism of Ac#on
D -Alanyl-D -alanine
H
ENZYME
H CH 3 O
N
Peptide
H CH 3
N
O
O
H CO2H
activated for nucleophilic
attack (peptidoglycan crosslinking)
H CH 3
N
Peptide
O
O
β-lactam antibiotics (penicillins)
are active site mimics
D -Alanyl-D -alanine
H
ENZYME
H H O
H
H
ENZYME
CH
S CH
H CH 3 RHO N3
3
N
N
Peptide Peptide
H
N
CH
CH
3
H O
3
N
ON CH 3O
O
H CO2H
O
O
H CO2HH CO2H
D -Alanyl-D -alanine
(natural substrate)
irreversible enzyme inhibition
activated for nucleophilic
attack (peptidoglycan Hcrosslinking)
H H
O S O
N
R
ENZYME
ENZYME
H CH 3
O
H
ENZYME CH
S 3 CH
H CHO3 R O NN
3
O
N
Peptide
CO2H CH 3
H HN
O
O
Penicillins
H CO2H
O
(substrate
mimic)
β-lactam antibiotics (penicillins)
are active site mimics
H
ENZYME
H H H O
S CH
N
R
3
O
N
O
CH 3
H CO2H
irreversible enzyme inhibition
O
H
N
R
O
TRANSPEPTIDASE (PENICILLIN BINDING PROTEIN)
O
H
H HN
ENZYME
S
CH 3
CH 3
H CO2H
β-‐Lactam An#bio#cs – β-‐Lactamases
β-lactam antibiotics (penicillins)
are active site mimics
H
ENZYME
H H H O
S CH
N
R
3
O
N
O
R
O
H
ENZYME
H H H O
S CH
N
R
CH 3
3
O
O
H
H HN
CH 3
CH 3
H CO2H
CH 3
H CO2H
irreversible inactivation of penicillin
O
H
N
ENZYME
S
N
O
H CO2H
irreversible enzyme inhibition
O
H
N
β-lactamase enzymes similarly
bind β-lactam antibiotics
R
O
O
H
H HN
ENZYME
S
CH 3
CH 3
enzyme
turnover (H 2O)
O
H
N
H CO2H
R
O
OH
H
S
H HN
CH 3
CH 3
H CO2H
TRANSPEPTIDASE
(PENICILLIN BINDING PROTEIN)
β-LACTAMASE
β-‐Lactam An#bio#cs – β-‐Lactamases
β-lactamase enzymes are inhibited
using a β-lactamase inhibitor
ENZYME
β-lactamase enzymes similarly
β-lactamase enzymes are inhibited
H
O
bind β-lactam antibiotics
using
H a β-lactamase
ENZYME
ENZYME inhibitor
IRREVERSIBLE
O
H
O
Clavulanic
H
OH
H
H
O
O OH
Acid
ENZYME
ENZYME
O
IRREVERSIBLE
INHIBITION
OH
H 2N
H O
O
H H H O
Clavulanic
H
H
OH
S CH
O
N
N
R
Acid
O
3
INHIBITION
HOCO
O
HN
2H
H CO2H N
O
N
CH 3
O
O
H CO2H
H CO2H
H
ENZYME
O
H H
OH O
ENZYME
H
H
O
O HN
ENZYME
OH H
O
H
H
ENZYME
irreversible inactivation of penicillin
O
H CO H
OH
O
O
2 O
H
HN
O
+
O
O
OH
H O
N
ENZYME
enzyme
H
H
O
H
turnover (H 2O)
H CO2H N
H+
S CH
N
R
H
3
H O
ENZYME
ENZYME
H CO2H
H HN
O
CH 3
OH
H H
OH
ENZYME
O
O
H
ENZYME
O
H CO2H
OH
H
H
O
H
H H
O
S CH
H
O
N
R
O
O
3
OH H
N
OH
O
N
H
H HN
O
O
CH 3
O
O
H H
H CO2H N
N
H
CO2H
H CO2H
O
H CO2H
H
H
β-LACTAMASE
J. Biol. Chem. 2005 Oct 21; 280(42), 35528-‐36
O
O
O
An#bio#cs

Lark J. Perez

β-‐lactam an#bio#cs and vancomycin con#nued
β-‐Lactam An#bio#cs – Natural Resistance

-‐ human cells (no pepLdoglycan in cell wall)

-‐ fungal cells (cell wall structure from chiLn)

-‐ some bacteria (speciﬁc and unique natural resistance)

Gram-‐negaLve bacteria inherently have some (typically lower) level of natural
resistance due to the outer membrane. Other examples include Mycobacterium
tuberculosis where mycolic acid layer blocks drug access to pepLdoglycan and
Chlamydia bacteria which are parasiLc spending part of their life cycle inside host cells
where they are inaccessible to the drug.

β-‐Lactam An#bio#cs – Acquired Resistance

1) β-‐lactamase producLon (Soluble, released enzyme…β-‐lactamase inhibitors help with this)
2) AlteraLons in porin size (In gram-‐negaLve bacteria smaller porins decrease the
permeability of the outer membrane prevenLng the drug from access to pepLdoglycan layer)
3) Eﬄux pumps (Energy dependent (e.g. ATP), acLve export of the drug from the cell)
4) MutaLons to the transpepLdase enzyme (Modiﬁed transpepLdase enzymes
which are sLll able to catalyze the crosslinking of pepLdoglycan but do not bind to penicillins.)

Conceptual approach to remembering resistance mechanisms:
1) Destroy the drug before it gets to the cell.
2) Don’t destroy the drug but prevent it from geing into the cell.
3) Let the drug in but once it has entered the cell, kick it out.
4) Change the biological target so it no longer ma,ers if the drug is present or not.

β-‐Lactam An#bio#cs – Penicillin An#bio#cs
H H H
N
S
R
N
R
R
ALL PENICILLINS
ARE BACTERIOCIDAL
O
OH
O
Penicillin Class (Penams)
Gram-positive
ONLY
NARROW
SPECTRUM
Very Narrow Spectrum
Natural
H H H
N
S
N
O
BROAD
SPECTRUM
O
O
CH 3
CH 3
O
N
Cl
O
Cl O
OH
penicillin G
O
N
O
O
penicillin V
N
O
dicloxacillin
H H H
N
S
O
H H H
N
S
Extended Spectrum
NH 2
CH 3
CH 3
O
ampicillin
NH 2
OH
H H H
N
S
O
N
OH
O
N
O
methicillin
O
CH 3
CH 3
HO
O
O
amoxicillin
S
O
N
O
O
ticarcillin
N
OH
CO2H
H H H
N
S
OH
O
H H H
N
S
O
anti-Pseudomonal
CH 3
CH 3
O
O
CH 3
CH 3
H H H
N
S
Gram-positive and
Gram-negative
CH 3
CH 3
OH
CO2H
H H H
N
S
O
N
O
carbenicillin
O
CH 3
CH 3
OH
CH 3
CH 3
OH
β-‐Lactam An#bio#cs – Penicillin An#bio#cs
H H H
N
S
R
N
R
R
ALL PENICILLINS
ARE BACTERIOCIDAL
O
OH
O
Penicillin Class (Penams)
Gram-positive
ONLY
NARROW
SPECTRUM
Very Narrow Spectrum
Natural
H H H
N
S
N
O
BROAD
SPECTRUM
O
O
CH 3
CH 3
O
N
Cl
O
Cl O
OH
penicillin G
O
N
O
O
penicillin V
N
O
dicloxacillin
H H H
N
S
O
H H H
N
S
Extended Spectrum
NH 2
CH 3
CH 3
O
ampicillin
NH 2
OH
H H H
N
S
O
N
OH
O
N
O
methicillin
O
CH 3
CH 3
HO
O
O
amoxicillin
S
O
N
O
O
ticarcillin
N
OH
CO2H
H H H
N
S
OH
O
H H H
N
S
O
anti-Pseudomonal
CH 3
CH 3
O
O
CH 3
CH 3
H H H
N
S
Gram-positive and
Gram-negative
CH 3
CH 3
OH
CO2H
H H H
N
S
O
N
O
carbenicillin
O
CH 3
CH 3
OH
CH 3
CH 3
OH
β-‐Lactam An#bio#cs – Penicillin An#bio#cs
H H H
N
S
R
N
R
R
ALL PENICILLINS
ARE BACTERIOCIDAL
O
OH
O
Penicillin Class (Penams)
Gram-positive
ONLY
NARROW
SPECTRUM
Very Narrow Spectrum
Natural
H H H
N
S
N
O
BROAD
SPECTRUM
O
O
CH 3
CH 3
O
N
Cl
O
Cl O
OH
penicillin G
O
N
O
O
penicillin V
N
O
dicloxacillin
H H H
N
S
O
H H H
N
S
Extended Spectrum
NH 2
CH 3
CH 3
O
ampicillin
NH 2
OH
H H H
N
S
O
N
OH
O
N
O
methicillin
O
CH 3
CH 3
HO
O
O
amoxicillin
S
O
N
O
O
ticarcillin
N
OH
CO2H
H H H
N
S
OH
O
H H H
N
S
O
anti-Pseudomonal
CH 3
CH 3
O
O
CH 3
CH 3
H H H
N
S
Gram-positive and
Gram-negative
CH 3
CH 3
OH
CO2H
H H H
N
S
O
N
O
carbenicillin
O
CH 3
CH 3
OH
CH 3
CH 3
OH
β-‐Lactam An#bio#cs – Overview
H H H
N
S
R
Defines Antibiotic
Spectrum Activity
CH 3
N
CH 3
Defines Antibiotic
O
SpectrumOH
Activity
O
Penicillin Class (Penams)
Very Narrow Spectrum
O
O
N
O
O
methicillin
O
O
N
O
O
methicillin
H H H
N
S
O
N
O
methicillin
O
N
O
CO2H
H H H
H H H
N
S
N
S CH
3
S
O
N
O
N
OCH 3
O
OH
O
O
methicillin ticarcillin
CH 3
CH 3
OH
O
CH 3…

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