Masters Degree Masters in Antibiotics Discussion

1. DQ 5. Each student should read the assigned reading, “A Brief History of the Antibiotic Era: Lessons Learned and Challenges for the Future.” This article provides a nice and succinct overview of many aspects of the “antibiotic era”. Create your initial post on the DQ 5 Discussion Board in response to the following:

DQ-6 Create your initial post on the DQ 6 Discussion Board in response to the following questions:Based on the assigned reading, “Antibiotics: Where did we go wrong?”. In this paper the authors provide an overview of some of the “drivers” of antibiotics R&D and they end their paper listing 8 key aspects of “Where did we go wrong?”. Pick ONE of these 8 key aspects of where we went wrong and provide additional details (from this paper and other referenced papers and/or additional references) to enhance our understanding of how what is meant by the authors listing this as a way we “went wrong”. Your post should contain the following:What aspect of “where we went wrong” did you pick? List based on the headings used by the authors in the assigned reading.Give a specific example of this aspect of where we “went wrong” in action. You should describe this example briefly and directly. Your example should be specific (i.e. a reference describing why a specific company stopped investing in antibiotics, a reference describing the emergence of “unexpected” resistance, a reference describing a shift in business structure for antibiotics.) Full reference for the example you found enhancing our understanding of specific ways in which we “went wrong” according to the authors of the assigned paper. After posting, return to the board and read over the posts of your fellow classmates. Choose at least one classmate and create a post commenting on his/her examples they provided to “where we went wrong”. You should comment on only ONE of your classmates “examples”. Only ONE student (first-come-first-served) is allowed to comment on each initial post, so every post should receive minimally one comment. You are not allowed to comment on your own post. Your comment should include the following…maybe we can reclassify the ways we “went wrong” together here:Classify the example your classmate gave of how we “went wrong” an example of a problem in:society/culturegovernment/legislation/administrationBusinessScienceother (define a category)Provide 1-2 sentences about why you categorized this “way we went wrong” the way you did.Give 1-2 sentences to describe a “solution” to the specific type of problem provided in the example you are commenting on. Note that your solution should match your classification of the example above. (e.g. Don’t suggest a scientific solution to a cultural problem!)https://www.sciencedirect.com/science/article/abs/… REVIEWS
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DDT • Volume 10, Number 1 • January 2005
Antibiotics: where did
we go wrong?
Karen M.Overbye and John F.Barrett
In the late 1960s, the medical need for new antibiotics began to be questioned, and
the pharmaceutical industry shifted its emphasis of antibacterials from that of a
therapeutic leader to a low-priority research area. Although infectious diseases, in
particular those caused by bacterial infections, are still among the top causes of
mortality in the world, industrial support continues to wane. The shift from this
important area of antimicrobial research has been attributed to a combination of
science, medical, marketing and business reasons. This decline in antibacterial drug
discovery, coupled with increasing risk as a result of infections caused by drugresistant bacterial pathogens, represents a clear public heath threat.
Karen M. Overbye
John F. Barrett*
Department of Infectious
Diseases,
Antibacterial Discovery,
Merck Research
Laboratories,
126 East Lincoln Avenue,
Rahway,
NJ 08876, USA
*e-mail:
john_barrett2@merck.com
Historically, the pharmaceutical industry capitalized
on the discovery that many microbial secondary
metabolites act as antibiotics [1–3]. The Actinomycetes,
which are isolated from soil, have provided the vast
majority of antibacterial compounds. Over 50 years
ago, the golden age of antibiotics dawned with
considerable achievements in the discovery and
development of the sulfonamides, penicillin and
streptomycin. This success was followed by the
characterization of the tetracyclines, macrolides,
glycopeptides, cephalosporins and nalidixic acid
[1–3]. Most of these compounds are either derived
from natural products or are produced by the
synthetic modification of natural products. The
compounds from this time period have provided the
basic scaffold for medicinal chemistry modifications
to expand the spectrum and/or potency of improved
analogs in subsequent years [1]. In the past 20 years,
over 50 antibacterial drugs have been developed,
and large pharmaceutical companies have supplied
generation after generation of improved antibiotics
characterized by these original classes of drug to
meet the existing medical need for novel agents with
antibiotic activity [4–10]. However, these numbers
are dwarfed by the number of new antibiotics
introduced in the preceding 20 years when antibiotics
were the mainstay of every large pharmaceutical
company.
Antibacterial therapy – a success story
The research and development of antibacterial
agents during the past 50 years has been an
immense success story. The rate of mortality caused
by bacterial infections has dropped precipitously
since the pre-penicillin days of the 1930s [11,12].
Although antibacterial agents, improved hygiene,
vaccines and an awareness of the bacterial cause
of various disease states are all believed to have
contributed to a lower morbidity and lower mortality worldwide, the major impact of these factors
on morbidity and mortality has been observed in
the industrialized world, where drug supplies have
been readily available. In 1967 and 1969, the US
Surgeon General, William H. Stewart, was reported
to have commented: ‘…that we had essentially
defeated infectious diseases and could close the book
on them [infectious diseases]…’ [13,14], and the
popular consensus of the time was that the unmet
1359-6446/04/$ – see front matter ©2005 Elsevier Ltd. All rights reserved. PII: S1359-6446(04)03285-4
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TABLE 1
Antibacterials currently in clinical development by large pharmaceutical companies
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Drug name or designation (company)
Class
Target
Status
ABT492 (Wakunaga)
Quinolone
DNA gyrase and topo IV
Phase Ia
WCK771A (Wockhardt)
Quinolone
DNA gyrase and topo IV
Phase Ia
PNU288034 [Pfizer (Pharmacia)]
Oxazolidinone
Protein synthesis
Phase Ia
Garenoxacin [BMS284756 (Schering-Plough and Toyoma)]
Quinolone
DNA gyrase and topo IV
Phase IIIa,b
Doripenem (Shionogi and Pennisula Pharma)
Carbapenem
Cell wall
Phase IIIa,b
CS-023 (Sankyo and Roche)
Carbapenem
Call wall
Phase IIa,b
Tetracycline
Protein synthesis
Phase IIIa,b
Tigecycline [GAR936 (Wyeth)]
a
b
Information acquired from: Investigational Drugs database; and company website, press release or analyst meeting. Abbreviation: Topo, topoisomerase.
medical needs of infectious diseases had been satisfied by
existing therapies, thus infectious diseases were of a lower
public health priority. Moreover, there was a subsequent
decline in broad-based industry support for antibacterial
and antibiotic research, which, together with the advent
of widespread chronic disease therapy (e.g. cardiovascular,
CNS, pain, arthritis and cholesterol-lowering agents), has
continued to decrease to its present state of minimal
backing from the large pharmaceutical companies. The
incidence of multidrug-resistant (or pan-resistant) pathogenic bacteria is on the rise [15–17]. The Infectious
Disease Society of America (IDSA) recently reported (July
2004) that in US hospitals alone ~2 million people acquire
bacterial infections each year, and in 90,000 cases these
infections have fatal outcomes (http://www.idsociety.org/
pa/IDSA_Paper4_final_web.pdf). In addition, >70% of the
bacterial species that cause these infections are likely to
be resistant to at least one of the drugs commonly used
in the treatment of bacterial infections. All this prompts
the question – where did we go wrong?
A snapshot of the antibacterial agents currently
available
Examination of the current status of potential novel
antibacterial drugs indicates that there are only a few
compounds in development by the large pharmaceutical
companies (Table 1), with the majority of candidates
coming from the smaller biotechnology pharmaceutical
companies (Table 2) [18,19]. In the past 30 years, the only
truly novel agents that have been launched are linezolid
(Pharmacia and Pfizer) and daptomycin (Cubist) [1,19].
Concomitant with the development of these novel
agents, there has been a decrease in the number of analogs
generated of the classical antibacterials, predominantly
penicillins, carbapenems, cephalosporins, tetracyclines,
macrolides and quinolones [4,5,11,18,20–25]. Between
1983 and 2001, 47 new antibiotics won approval by the
US FDA or the Canada Health Ministry (http://www.fda.
gov/cder/approval/index.htm; http://www.idsociety.org/
pa/IDSA_Paper4_final_web.pdf). Only nine new antibiotics
have been approved since 1998, of which just two had a
novel mechanism of action. In 2002, there were no new
antibacterials in the list of almost 90 drugs approved by
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the FDA and, in 2003, there were just two antibacterials
approved (http://www.fda.gov/cder/approval/index.htm).
Of the ~550 drugs currently in development, only six are
novel antibiotics (Table 2) [26,27].
What has become of ‘big pharma’as the driver of
antibacterial research?
Fifty years of medicinal chemistry efforts centered around
~12 antibacterial core chemotype scaffolds have resulted
in the development and marketing of >200 antibacterial
agents [1,2,28]. Although no new major chemotype
scaffolds have emerged, with the possible exception of
the oxazolidinone synthetic core (e.g. linezolid), the
lipopeptides (i.e. daptomycin) and the ketolides (i.e.
telithromycin), which are modified macrolides, have been
developed to address emerging resistance problems
[29,30]. Many large pharmaceutical companies have reprioritized their R&D efforts to either de-emphasize or to no
longer include antibacterials and/or antifungals, while
many maintain their support of R&D into antivirals
[18–20,27,28]. In the past five years, companies such as
Wyeth, GlaxoSmithKline, Bristol-Myers Squibb, Abbott
Laboratories, Aventis, Eli Lilly and Proctor and Gamble
have de-emphasized or abandoned their endeavors in
antimicrobials, whereas Novartis, AstraZeneca, Merck,
Pfizer, Johnson and Johnson and others continue to
promote internal antibacterial discovery efforts. Meanwhile,
a large number of biotechnology organizations continue
to support antimicrobial R&D, but are faced with increasing financial pressures, which have led to many companies ceasing operations [19]. This situation raises the
question – is this effort enough?
The rise of the biotechnology company
As the emphasis of antibacterial R&D efforts has shifted
away from many large pharmaceutical companies to a
large contingent of biotechnology companies, the entrepreneur approach to discovery has led to an explosion
of creativity in strategies, selection of targets, genomics
and development paradigms. The output of this effort is
a pipeline of primarily novel, but niche, antibacterials
in varying stages of clinical development (Table 2). On
examination of the models used by these companies, a
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DDT • Volume 10, Number 1 • January 2005
TABLE 2
Drug name or designation (company)
Class
Target
Status
MC02479 [RWJ54428, RWJ442831a (Trine and J&J)]
Cephalosporin
Cell wall and transpeptidation
Phase Ib
MC04546 [RWJ333441, RWJ333442a (Trine and J&J)]
Cephalosporin
Cell wall and transpeptidation
Phase Ib
VRC4887 [LBM415 (Vicuron and Novartis)]
Hydroxamate
Peptide deformylase
Phase Ib,
BB83698 (Vernalis, Genesoft and Oscient)
Hydroxamate
Peptide deformylase
Phase Ib,d
Ramoplanin [GTC (Oscient) and Vicuron]
Glycolipodepsipeptide
Transglycosylation and lipid II
Phase II–IIIb,c
Oritavancin [LY333328 (Intermune and Lilly)]
Glycopeptide
Cell wall
Phase IIIb,c
Rifalazil (Activbiotics)
Benzoxazinorifamycin
RNA polymerase
Phase IIb,c
BAL5788 (Basilea and Roche)
Cephalosporin
Cell wall
Phase IIb,c
MC04,124 (Mpex Pharm, Trine and Daiichi)
Peptide
Efflux pump inhibitor
Preclinicalb,c
MP601,205 (Mpex Pharm and Daiichi)
Peptide
Efflux pump inhibitor
Preclinicalc
Dalbavancin (Vicuron and Aventis)
Glycopeptide
Cell wall
Phase IIIb,c
TD6424 (Theravance)
a
Lipoglycopeptide
b
Phase IIb,c
Cell wall
c
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Antibacterials currently in clinical development by biotechnology companies
d
Prodrug of active component. Information acquired from: Investigational Drugs database; and company website, press release or analyst meeting. Discontinued development.
Abbreviation: J&J, Johnson & Johnson.
pattern becomes apparent. The observed trend is a combination of the acquisition of niche products that have
not been developed by larger pharmaceutical companies,
the exploitation of scientific discoveries not successfully
applied to drug discovery by larger pharmaceutical companies and an incremental improvement in an existing
class of agents. Surprisingly, none of the large pharmaceutical companies have successfully developed the novel
targets approach to identifying drug candidates. The
premise of this failed novel targets approach is generally
based on attempts to exploit the ‘genomics’ technology
that launched after the start of the whole-genomesequencing era in the mid- to late-1990s. However, two
biotechnology companies have managed to progress nongenomics program drugs to the market. These two success stories are the lipopeptide Cubicin®, an intravenous
hospital drug for the treatment of serious Gram-positive
infections, which was developed by Cubist and approved
for therapeutic use in 2003 [22,31], and the quinolone
Factive® (gemifloxacin), used for respiratory tract infections, which was developed by Oscient and was also
approved in 2003 [31].
Although the drugs that are approved, or are soon-tobe-approved, might represent breakthrough therapy, the
overall product profile of the biotechnology organizations
developing these novel agents fits more of the niche
market treatment options than broader or empirical use.
Narrow-spectrum agents are generally not considered to
be as commercially attractive by the majority of large
pharmaceutical companies when compared with the commercial potential of drugs for the treatment of other therapeutic areas. Because most therapeutic agents are used
in empiric therapy, there will need to be a drastic change
in treatment paradigms or a major improvement in the
diagnostic area to promote increased interest in niche
antibacterial markets. Broad-spectrum, well-tolerated
agents that address emerging resistance will continue to
be the focus of the remaining key pharmaceutical industry
players. Another problem that biotechnology companies
currently face is the significant capital that is necessary to
undertake large-scale clinical trials. Most biotechnology
companies cannot undertake the costs of these clinical
trials alone, and for many such companies the new business model for survival appears to be to move forward
with single, key indications that will provide a steady
revenue stream upon first regulatory approval to market
their drug. Unfortunately, when the biotechnology company cannot find a development partner to bear the high
cost of Phase II–III trials, the result of this plan has
frequently been to dispose of discovery assets (including
people) to pay the cost for clinical development. This is
not a sustainable business model.
The essentials of antibiotic and antibacterial discovery
As with any other therapeutic area, antibiotics requires a
novel starting point to spark interest, the perception of
do-ability and a sustained commercial value potential in
pursuing antibacterial R&D. Historical nomenclature
has antibiotics as derivatives of natural products [32] and
antibacterials as products of synthetic chemotypes. The
process of discovery is similar in all therapeutic areas
involving synthetic or semi-synthetic molecules, but is
different from biologics (which will not be considered
further here). A key distinction between antibacterials
and antibiotics and chronic disease therapy has been the
reliance on natural products for a chemotype starting
point [2,21,26], with several important exceptions such
as the natural product-based statins, multiple cancer
agents and some immunosuppressive drugs [35]. In the
past two decades, the greatest probability of short-term
success has come from improving the existing, safe and
proven classes of antibacterial agents – but this strategy
no longer commands a premium price in the market
to justify the investment. With the almost complete
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withdrawal of the large pharmaceutical companies from
natural product sourcing for antibiotics, the R&D discovery
units turned to pre-existing synthetic libraries of compounds made primarily for other purposes; this approach
has frequently identified excellent target inhibitors in HTS
(and analog programs), but few with antibacterial activity
(usually as a result of permeability issues in transporting
inhibitors across bacterial cell membranes).
What changed in the ‘value’of antibiotics and
antibacterials?
There are numerous factors that have an impact on the
‘value’ of antibiotics in the marketplace, including: (i)
increase in antibacterial sales (both percentage increase
and overall dollars); (ii) generics; (iii) segmentation (specialization of the market); (iv) increased regulatory hurdles
and postlaunch commitments; (v) total R&D cost versus
‘return on investment’ (ROI); and (vi) the competition for
resources within the pharmaceutical industry for R&D
areas limited by capital available (i.e. should constrained
resources be used to develop antibacterials versus chronic
drugs?) [19,20,27,28].
Whereas the recent successes of chronic disease drugs
(e.g. statins, CNS agents, pain relief, asthma treatment,
arthritis relief and erectile dysfunction drugs) provide a
stark contrast in their relatively limited numbers of drug
classes (when compared with the history of antibiotics
R&D), these chronic disease treatment areas have an
advantage in the way in which they are used (i.e. life-long,
pill-a-day therapy). By contrast, antibiotics are administered in predominantly acute situations to reduce infection
and prevent mortality; thus, the numbers of patients-days
(total number of days an individual patient is on drug
therapy) for antibiotics is dwarfed by drugs for chronic
indications in the same patient population in the industrialized world [19].
There is also a lack of appreciation for the untold cost
of bacterial resistance development in the microbial community and its effect on clinical efficacy of antibiotics
[12,34–46]. Resistance, which is inherent in the mode-ofaction of all antibiotics and antibacterials, poses challenges in the development of new antimicrobial agents
by large pharmaceutical companies, as well as biotechnology companies. The majority of antibiotics and antibacterials have an ‘inherent obsolescence’ because of the
emergence of resistance by virtue of the target they attack
[34,42–46]. Unlike chronic drug therapy, where an efficacious drug can be used indefinitely without ‘resistance’
to that drug lowering efficacy, the action of antibiotics
facilitates the selection of mutant bacteria, which arise as
resistance pathogens during the normal course of therapy [9,45,47,48]. Thus, antibiotics are unique in that their
extensive use in clinical therapy will lead to an inevitable
decrease in drug benefit, both for the individual drug and
the entire class of drugs that act via the same mechanism.
Increased resistance usually accompanies the wide use
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of newly approved antibacterial agents and, typically, resistance has been identified within just four years of FDA
approval of the drug [28]; linezolid is the latest example
of this pattern, with resistance to this antibiotic initially
occurring in clinical trials.
These emerging pathogens represent a real public
health threat [2,12,15–18,22]. This can be seen in numerous surveillance programs worldwide, which provide
researchers and clinicians with data on the susceptibility
trends, as well as presenting drug discovery researchers
with an indication of existing problems and a projection
of future needs [36–41,49,50].
In the hospital setting, the re-emergence of Gramnegative pathogens is of major concern [2,12,15–17,28].
In one large study, >60% of the sepsis cases were caused
by virulent Gram-negative bacteria (e.g. Pseudomonas
aeruginosa, Klebsiella pneumoniae, Escherichia coli and
Enterobacter spp.) [34,38,39]. In addition, emerging
resistance among ‘newer’ pathogens, such as Acinetobacter
baumannii (once thought to be an environmental contaminant and now seen as a serious opportunistic
pathogen in hospitals) also presents significant and growing medical concerns [40], as do older pathogens such
as methicillin-resistant Staphylococcus aureus, Streptococcus
pneumoniae, Salmonella typhimurium and Mycobacterium
tuberculosis [35,37,43,50,51]. In 1993, the World Health
Organization (WHO) declared M. tuberculosis to be a global
emergency [12], the first such designation ever made by
the organization. According to the WHO, one individual
becomes infected with M. tuberculosis every second, and
every year eight million people contract the life-threatening disease [12], of which two million die. The WHO
predicts that between 2000 and 2020, nearly one billion
people will become infected with M. tuberculosis and this
disease will cost a total of 35 million people their lives. The
impact of HIV infection as a co-factor in M. tuberculosis
prevalence [51] necessitates that efforts be taken now to
avoid a catastrophe in the next 20 years.
Antibiotic versus antibacterial scaffolds for drug
development
The starting point for virtually all natural products that
have become antibiotic scaffolds is that they possess one
or more target-inhibition sites, and that the bacterial
membranes are permeable to such natural compounds
[1,16,21,26,32]. Many of the attempts to identify novel
antibacterials have been disadvantaged because the
approach has optimized target activity only (i.e. nM Ki
values of inhibitors that do not have activity against
bacteria). Without a bacteria-permeating lead as a starting
point, and no knowledge of the SAR of the ability of the
lead to permeate the bacterium, multiple industrial
programs have produced nM inhibitors that failed to
penetrate into the bacterium. There have been numerous
reports of nM levels attained for enzyme inhibitors,
for example, alanine racemase, that are precluded from
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Where did we go wrong?
Analyses of the synopsis of factors that drive the support
of antibacterial R&D now enables consideration of the
question at hand – where did we go wrong? Apart from
the judgmental nature of the question (i.e. point the
finger at other individuals), there are at least eight key
aspects that enter into a thorough answer.
Shifting priorities by business
The change in emphasis and/or support of antibiotics is
a combination of the changing market potential and a
shift away from the guaranteed success of ‘me-too’
analogs of classic chemotypes to the high-risk, new target
and non-natural product-sourced antibacterial leads that
have produced few success stories. This has prompted a
continuous, serious business review of the value of the
only guaranteed renewable research area (i.e. inherent
obsolescence as a consequence of resistance emergence),
and more pharmaceutical companies could discontinue
antibacterial R&D. Undoubtedly, when the first wave of
the blockbuster chronic disease drugs lose exclusivity, a
repeat of this paradigm will be observed, which might
level the playing field in valuing antibacterials.
Under-appreciation of resistance
Resistance evolves in bacteria because of the nature of
their high growth rate (i.e. doubling time) and their ability to select for bacterial survivors in a population that
have spontaneous mutants. Bacterial mutants with enhanced ability to survive in the presence of the environmental insult (including antibiotics) will constantly be
emerging in the microbial ecology. Unlike bacteria, eukaryotic cells rarely evolve within the lifetime of a therapy to a ‘resistant state’ (with the exception of the lower
eukaryotic fungal cells and some cancer resistance mechanisms). Thus, in the drive for originality in the blockbuster areas of ‘met medical need’, those institutions that
cover the consumer cost of drugs will require strong convincing to use a new generation chronic disease agent
over the older effective generic chronic drug treatment.
By contrast, antibiotic innovation is the definitive solution to the increasingly difficult-to-treat bacterial infections that are caused by antibacterial-resistant pathogens.
Therefore, the treatment of drug-resistant pathogens
represents a renewable unmet medical need, but does not
yet represent a significant commercial opportunity for
industry.
Seduction of genomics and forgetting how to ‘make’
a drug
The seduction of genomics of the mid-1990s has led to
unsuccessful industrial efforts to exploit novel bacterial
targets. Well-defined, ‘classical’ targets were replaced
overnight with a wave of novel genomic targets, which
were subsequently matched to totally new chemotypes as
leads, and the new paradigm was predicted to be more
successful than classical approaches to antibacterial drug
discovery. We were wrong!
Beginning with the delivery of the Haemophilus influenzae genome sequence in 1995 [57], numerous pharmaceutical firms quickly understood that this sudden
influx of microbial genome data could be mined for sets
of novel targets for antibiotic and vaccine development
[58–62]. In addition, advanced computational tools and
innovative genomic strategies such as DNA microarrays
for gene message expression analyses [63,64] and proteomic analyses [65,66] provided ‘validation’ of several
dozen novel, essential, broad-spectrum targets. However,
to date, not one ‘genomics’ target has been exploited to
the point of reaching clinical trials. Although the hope of
genomics-based drug discovery could offer an alternative
strategy in the future, these tools of microbial genomics
are just a part of the successful execution of identification
and development of novel antibacterials.
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being engineered to become antimicrobials because of
their inability to penetrate the bacterium adequately.
[3,21,52].
The manufacture of secondary metabolites by ‘producer
organisms’ in nature is believed to support multiple functions, including the ability to communicate with other
microorganisms and to protect the organism from attack
[26,33,53,54]. If the microbial strategy is to protect the
producer organism, it is logical that antimicrobials would
be identified in nature under adverse conditions because
their production would assure and/or enhance the survival
of the producer organism from environmental insult.
Thus, the rich source of antibiotic activities in nature
(some that have selectivity over eukaryotes and others
that do not) is understandable in terms of structural
design from an evolutionary survival standpoint – and
represents a great sourcing pool for novel chemotypes.
However, the field of industrial natural product sourcing
has been eliminated from the best practices of the large
pharmaceutical organizations because of: (i) a lack of
more-recent successes; (ii) the promise of genomics and
HTS screening; (iii) the potential of rational drug design
based on structural work; and (iv) the possibilities associated with combinatorial chemistry [1,20,26,32,33,55].
Furthermore, it is now known that conventional techniques
for cultivation only enable the isolation and growth of a
small subset of all microbial life forms identified in nature [56]. Ironically, natural product scaffolds were used
to construct many of the first-generation chronic disease
drugs, such as cardiovascular agents (e.g. digoxin, digitoxin and lanosterides), anticancer agents (e.g. bleomycin,
doxorubicin, vincristine, mitomycin, paclitaxel and
camptothecin), CNS agents (e.g. codeine, morphine,
physostigmine and galanthamine), immunomodulatory
agents (e.g. cyclosporine and FK506) and cholesterol-lowering agents (e.g. simvastatin, pravastatin and lovastatin)
[33].
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Industrial shift from natural product sources for novel
chemotypes
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The abandonment of natural products by most industrial
groups is a mistake, because the leads identified in natural
product sourcing for antibiotic scaffolds often provide a
starting point for medicinal chemistry. This subsequently
leads to the search for the target, the identification of
which is typically achievable because the nature of the
natural product compound is such that it has a structure
that enables it to permeate the bacterium. Medicinal
chemistry builds on a SAR with pre-existing antibacterial
activity, enabling optimization of other ‘drug-like’ properties without having to discern how to transport the
lead across the bacterial cell wall and/or membrane.
Consequently, beginning with an ‘antimicrobial’ as a lead
has proven the most successful approach to date in the
discovery of antibiotics [1,26]. Over the past 30 years, only
the oxazolidinones have a totally synthetic history, but
even the quinolones evolved accidentally from a distinct
natural product scaffold for malaria [33,67]. If the path to
the discovery of nalidixic acid (the progenitor of the
successful fluoroquinolone class) is examined, it can be
seen that the major antimalarial drugs (chloroquine,
mefloquine and primaquine) were all derivatives of
the alkaloid quinine (which can be found in the South
American tree Cinchona succiruba [68]). This quinine
nucleus, which was subsequently synthesized in the
laboratory, was the scaffold from which nalidixic acid (a
1,8-naphthyridine) was identified as an unintentional
by-product by chemists at the Sterling Drug Company
[33], and it was this product that formed the basis for the
synthesis of new antimalarials; these agents later formed
the synthetic core for the fluoroquinolones [68].
Multivariable problem in need of an integrated,consensus
solution
As an ‘industry’, we have fallen behind the evolving
decrease in susceptibility of major pathogens to antibiotics
and antibacterials and the foothold they have in the
clinic. All ‘stakeholders’ have a part in this general
‘industry’ term, including those that discover and develop
drugs, those that approve drugs for licensing, prescribe
drugs for infections and the administrators and/or payers
of the cost expenditures for antimicrobial therapy. The
position the industry finds itself in is the ‘wrong’ of all
participants, which will be solved only by significant
change in its approach to dealing with bacterial infections.
There are multiple initiatives underway to address this
problem, including efforts by the IDSA, WHO, National
Institutes of Health and regulatory authorities (among
others) to convene meetings with key opinion leaders in
an attempt to build a consensus solution.
Complacency
Complacency might be a good term to cover several
aspects of the ‘norm’ established in the first 30–40 years
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of antibacterial R&D. Among these norms were: (i) the
belief that there are always other analogs with superior
qualities to be sold (i.e. β-lactams and tetracyclines); (ii) the
conviction that a ‘fast follow-on’ was the same as me-too
drugs (e.g. the success of Levaquin® argues otherwise –
the development of the single L-isomer of the racemic
ofloxacin mixture led to increased potency, efficacy,
improved dosing and enhanced safety profile); (iii) new
analogs will enable antibiotics to stay ahead of the
bacterial resistance curve; and (iv) the opinion held by
industry, academia, the medical community, regulatory
authorities and commercial groups that ‘failure’ to execute
is the same as ‘chance of success’ (a number calculated by
historical metrics to benchmark success rates). That is to
say, there has been a repeated failure to deliver new
antibacterials to the marketplace, but this factor is only
one of many used to prioritize research efforts. There must
be a significant improvement in efficacy, safety, cost
and/or compliance to command a premium price and
deep penetration in the marketplace.
Who can blame be assigned to?
Is the pharmaceutical industry culpable for the current
situation? The industry most probably would be deemed
a ‘success story’ for most of its history, but mistakes have
been made in underestimating and/or misunderstanding
a changing marketplace, failing to appreciate the force of
resistance on the erosion of efficacy in particular drug
classes and missing the changing paradigm that managed
care brought to the marketplace (i.e. facing a satisfied and
segmented market and the impact of generics in lowering
the perception of ‘value’ of antibacterials). Lessons have
been learned, including that novel disease states (predominantly chronic diseases) offer an easier path to success and that incremental improvements in analogs of existing drugs will be essential with a higher ‘quality’ bar to
compete in a satisfied market. In addition, genomics
could identify new targets and disease states, but the identification of a viable, antimicrobial starting pharmacophore is the key factor for success. It appears that the
industry as a whole has lost the innovative edge in antimicrobial discovery research that it once had.
Diagnosis
As a business group, the pharmaceutical industry has not
succeeded at some key aspects of the discovery of antibacterials and antibiotics. The industry has failed in the
continuous production of novel, high-quality, efficacious
and safe ‘products’ since the early-1980s. Furthermore,
it has not succeeded at several tactical processes (i.e. hitsto-leads and lead optimization); it has erred in strategically choosing synthetics over natural products as the sole
source for the majority of new leads; and it has been seduced by the lure of genomics and has wasted many years
chasing sub-optimal leads against ill-defined targets simply because the targets were genomically-identified and/or
validated or ‘novel’. The industry has also underestimated
the hardiness of serious pathogens to survive and to adapt
resistance mechanisms against the best antibacterials,
while continuing to expose normal flora and opportunistic pathogens to existing drug classes, resulting in
underlying resistance in emerging pathogens. In short,
the industry has not got the job done in recent times. This
must change.
Conclusions
There is a serious unmet medical need for new antibacterial agents to treat drug-resistant infections [69]. The
underlying resistance to antibiotics in emerging pathogens
might be selected for by drug exposure in prior rounds of
antibiotic therapy; this latent resistance is potentially a
major problem to be addressed in the near future. Only
the successful identification and development of novel,
potent, efficacious antibacterial agents will solve this
problem. Reinvigorated, sustained efforts by multiple,
large pharmaceutical companies, either directly or in
partnership with biotechnology companies, to support
clinical trials will drive this situation to a successful
paradigm again.
The industry has simply not delivered novel antibacterials, however, the diverted resources have had a major
positive impact on the treatment advances for chronic
disease states, including both life-threatening (e.g.
cardiovascular, lipid-lowering, asthma and cancer) and
quality-of-life (e.g. anti-anxiety, anti-depression, antiemisis and erectile dysfunction) drugs. There has been no
clear vision for the importance of antibiotic resistance and
the constantly evolving marketplace expects safer and
broader spectrum and/or coverage from the new agents.
Furthermore, the prioritization of resources has been
driven by a lack of commercial ‘value’ of antibacterials
and the lure of treating chronic diseases. In the past 5–10
years, multiple attempts have been made to exploit novel
antibacterial targets, and virtually all have been unsuccessful. This could be viewed as ‘…the drug industry gone
wrong…’ or it can be seen as a logical shift of resources
that will enable the industry to survive as a business
entity.
Perhaps our perspective as members of the industry
should be one of ‘shared success’ and ‘shared culpability’.
The emergence of resistance has brought the industry to
the point of requiring severe paradigm shifts in how antibacterials are developed and brought to the marketplace.
The ‘blame’ can be assigned to individuals or all the players involved, but this accomplishes nothing in facilitating a solution. Perhaps the way to move forward is to
admit shortcomings (through a process of gleaning ‘lessons learned’ from past experiences) and to advance
towards a joint, universal solution to convince the pharmaceutical industry to reinvest support in antibacterial
R&D. A non-judgmental, broad-based consortium of multidisciplinary, multiorganization key opinion leaders must
be mounted to forge a sustainable plan for reversing these
undesirable trends without pointing the finger at the most
convenient partner. To the question – where did we go
wrong? – there might not be a consensus answer, but
there must be a consensus solution. If a resolution is to
be reached, the ‘pre-antibiotic’ scenario that key infectious disease specialists have warned of for many years
might have to be faced.
Acknowledgement
We would like to thank Christine Jenkins for her administrative and editorial support in assembling this manuscript.
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