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Antibiotics at the crossroads
The public takes for granted that the pharmaceutical industry can anticipate society’s
medical needs and meet them. This faith is
nowhere more evident than in the expectation that antibiotics are readily available to
treat bacterial infections. After all, infectious diseases are the second-leading cause
of death worldwide and the third-leading
cause of death in economically advanced
countries. But surprisingly, despite growing
bacterial resistance to existing drugs, antibiotic development in the pharmaceutical
industry is steeply declining (see chart,
right)1–3. This new problem is converging
with an old one — the scarcity of antibiotics to treat diseases prevalent mainly in
poorer regions.
The emerging crisis in wealthy nations
and the long-standing crisis in poor nations
result from the same causes — economic,
regulatory and scientific — each exacerbated
by the problem of antibiotic resistance.
Government agencies and professional
societies have addressed the latter problem3–6, but little has changed. We need new
approaches, beginning with the recognition
that the antibiotic crises of wealthy and poor
nations are the same. The challenge is this:
what can we do about the level of antibiotic
research and development, which has long
been insufficient to meet the needs of most
populations, and now is plummeting?
Causes of this decline are reviewed below,
followed by ‘blue sky’ proposals for a more
constructive approach to the permanent
struggle with infectious disease. The focus is
on drugs, but vaccination has a major role to
play in reducing dependence on antibiotics.
Economic pressures
With respect to profit margins, financial
markets hold the pharmaceutical business
to a higher standard than almost any other
industry. The demand for blockbuster
drugs pressures companies to focus on
long-term treatment of chronic conditions
in preference to brief treatments for bacterial
infections7. Most of the antibiotics that
major firms make are designed for broadspectrum activity, so that they can be used
by as many patients as possible. This shortens the market life of an antibiotic — as
widespread use of an antibiotic hastens the
emergence of resistance against it. To ward
off resistance, physicians are urged to spare
their use. With profits thus restrained in the
medical arena, pharmaceutical firms send
roughly half their antibiotic output to the
The lack of new drugs leaves children in developing
countries especially vulnerable to disease.
Total number of new antibacterial agents
16
14
12
10
8
6
4
2
0
1983– 1988– 1993– 1998– 2003–
1987 1992 1997 2002 2004
food industry5. Pork, fowl, fish and dairy
producers use antibiotics to maintain stock
and foster growth. This selects for resistant
bacteria, which can find their way into
human populations — hastening the demise
of the drug and making once-treatable
infections incurable4–9.
Industry’s retreat from developing new
antibiotics is leading to a loss of expertise in
both practical and theoretical aspects of
antibiotic biology1. As industry reassigns or
retires its microbiologists, academia will in
turn train fewer5. When wealthy societies
demand a resumption of antibiotic research,it
will take years to rebuild the knowledge base.
Better business models
The Global Alliance for Tuberculosis Drug
Development, a not-for-profit agency, is
building a case to persuade industry that
moderate profits can be made by developing
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antibiotics for a disease prevalent in poor
regions10. AstraZeneca has opened a research
centre for anti-tuberculosis drug development in India (www.astrazenecaindia.com)
and GlaxoSmithKline has assembled a team
to work on drugs for tuberculosis and malaria (www.gsk.com/financial/reps02/CSR02/
GSKcsr-7.htm). Although these are positive
steps, these initiatives are not enough to
equip us to treat infections endemic in poor
regions, nor do they address the emerging
shortage of antibiotics for bacterial infections in wealthy nations.
Academic scientists are making rapid
advances in the chemical biology of infectious
diseases. But they lack access to medicinal
chemistry, pharmacology and the expertise
to turn ‘hits’ into drug leads, or those leads
into drugs.
What is needed is a new player on the
scene: a not-for-profit drug company. The
profit sector could provide leadership.
Encouraged by tax incentives,industry could
give sabbaticals to its scientists and executives to work at a not-for-profit firm in
rotation. Many in the pharmaceutical industry would like nothing better than to contribute personally to an endeavor in which
their company (as a whole) is constrained
from engaging.
A not-for-profit firm could pursue
research differently, protecting its intellectual property by filing patents, but also advertising its work openly,with the goal of licensing
the intellectual property gratis to any company or agency that commits to produce and
distribute the resulting drugs on a basis that
would serve the needs of patients and society.
For example, distribution in low-income
markets could be on a for-cost basis whereas
distribution in wealthy markets could
remain for-profit.
Biotechnology firms are beginning to
‘translate’ the ideas of academic researchers
into drugs, but it is difficult for small firms to
mount a world-class effort at medicinal
chemistry and pharmacology, especially
now that expertise in antibiotic development
is scarce. A not-for-profit drug company
could perform these services in exchange for
a share of revenues from sales in highincome countries, coupled with a commitment that the drugs be distributed on a
not-for-profit basis elsewhere.
The best established way to delay the
emergence of antibiotic resistance is to use
one or more drugs in combination —
known as combination therapy. A potential
source of income for a not-for-profit, industry-supported drug company could there899
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C. MOLLOY/SPL; SOURCE: CLIN. INFECT. DIS.
Carl Nathan
A. CRUMP, TDR, WHO/SPL
Are we making the right choices to bring new drugs to the marketplace?
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AstraZeneca's research operation in Bangalore brings much-needed investment and expertise to India in the search for anti-tuberculosis drugs.
fore be contract work for private firms to
identify effective drug combinations at an
early stage. In fact, a not-for-profit firm
could test the idea that shared knowledge
allows early identification of targets (usually
microbial enzymes) whose combined inhibition is lethal to the bacteria.
The majority of the funding for a nonprofit firm would probably have to come
from government and foundations. Tax
incentives could encourage the for-profit
sector to furnish services in kind or at cost,
including equipment, supplies, chemicals,
clinical development, and regulatory and
legal services. Manufacturing could be
contracted to factories in low- and middleincome countries.
One can foresee many problems, such as
back-flow of drugs from poor regions to
wealthy ones. Such problems will be easier to
manage than asking twenty-first century
societies to accept nineteenth-century death
rates from infection3.
Regulatory obstacles
Another major disincentive in the development of new antibiotics is the current system
of regulatory requirements that discriminate
against their approval1,5. In the United States,
companies must demonstrate that a new
antibiotic is superior to existing agents when
used against infections caused by drug-sensitive strains. Existing agents are so effective
against drug-sensitive strains that a new
antibiotic is unlikely to be much better than
an older one. Yet testing new antibiotics
against infections caused by antibiotic-resistant bacteria is exceptionally difficult, as
patients with serious drug-resistant infections have usually been treated with other
antibiotics before resistance is documented.
In short, the regulatory system is geared to
generic standards of
safety and
efficacy — it makes no allowance for the specific case of antibiotic resistance. Companies
have withdrawn from developing products
against which they believe the regulatory
system discriminates.
Smarter regulations
In agreement with recent recommendations3
of the Infectious Disease Society of America
(see news feature on page 892), I believe
regulatory requirements and patent incentives should be revised to encourage the
pharmaceutical industry to develop new
antibiotics. New antibiotics should be
approved if they meet three tests. First, the
safety profile is acceptable for the severity of
the infection; second, the drug is effective in
patients against antibiotic-sensitive bacteria; and third, the drug is effective in vitro
against bacteria that are resistant to one or
more existing antibiotics used to treat that
infection. After a new antibiotic is
approved, its clinical efficacy should be
monitored in patients who are infected with
bacteria resistant to previously approved
antibiotics. This information should be
posted on the Internet as it is collected.
Unless new antibiotics are used in combination, resistance8 against them will quickly
arise.A new pre-approval test should be developed for antibiotics intended to treat persistent or recurrent infections,such as tuberculosis and malaria, which require sustained
administration.The manufacturer should run
preclinical tests to determine how the new
agent interacts with existing antibiotics used
to treat that disease (one from each class).This
information, combined with the drug’s pharmacokinetic profiles,should help regulators to
develop new post-approval requirements for
treating patients. First, the manufacturer
should specify lists of agents, at least one of
which should be used together with the new
drug.Second,the manufacturer should monitor clinical efficacy and incidence of drug resistance when such combinations are used in
practice.
Patent life should be extended for antibiotics of new chemical classes directed at new
targets2,analogous to US patent extensions for
drugs developed to treat rare genetic diseases.
In addition, all new antibiotics should be
banned from widespread administration to
healthy animals. It remains for the rest of the
world to embrace an enforceable version of
the ban enacted in the European Union in
1998 (ref. 6), or alternatively, to provide tax
incentives with the same effect.
Stalled science
It would be simplistic to blame market
forces and regulatory requirements alone
for the antibiotic crisis. There is another
and more surprising cause — industrial
research and development has mainly
produced variants of older antibiotics,
when new drugs are sorely needed. Over the
past few decades, only two new chemical
entities have entered clinical practice as
antibacterial agents, and only one whose
target is in a new biochemical class1,2,8,9. It is
surprising that the well has gone dry,
despite heavy investment to dig it deeper
using combinatorial chemistry and computational biology. Although genomic analyses
are revealing hundreds of potential targets
in pathogens, it remains a fact that almost
all agents used to treat bacterial infections
either have unknown enzymatic targets or
target just four classes of enzymes — those
involved in synthesis of protein, nucleic acids,
cell walls or folate8. How did yield decline
while knowledge grew and tools improved?
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The answer may lie in a set of premises that
were so successful that they hardened into
dogmas. In a time of rapid intellectual expansion, dogmas are constraints.
Fresh approaches
There is no longer any reason to confine
ourselves to drugs that inhibit the synthesis
of protein, nucleic acids, cell walls and
folate simply because such drugs have been
so successful. We must find new microbial
targets. First, synthesis offers too narrow a
set of targets. Macromolecules such as DNA
and protein have life cycles. Birth need not
be the only point of intervention, as processing, repair and degradation are also
points of vulnerability. This is the rationale
behind efforts to target the proteasome in Overuse of antibiotics in livestock has led to an
Mycobacterium tuberculosis12.
increase in resistant bacterial strains.
Another broad set of targets are the
enzymes of core metabolism (intermediary conditions defining essentiality are multiple.
metabolism, energy generation and For example, many infections, including
micronutrient acquisition) in the bacteria. A tuberculosis, enter phases of latency — a
third set of targets (overlapping the other state of equilibrium between the bacterium
two) are the enzymes that enable the and the host response. The agents now used
pathogen to resist the defences of the host. to treat tuberculosis kill rapidly growing
After all, evolution has had more time than bacteria in culture within hours. In contrast,
scientists to select chemicals to kill treatment of tuberculosis in people takes
pathogens; the host has reactive oxygen at least 6–9 months of daily combination
intermediates, reactive nitrogen intermedi- therapy, because the microbial targets that
ates and pore-forming peptides in its arsenal. are essential in exponential growth phase
Of course, evolution has also strengthened may not be so critical during latency or
microbial defences against the host’s persistence5.
chemistries. But we can aid the host’s
Systematic studies in yeast teach us that
immunity by using
mutations in many
antibiotics that disable
genes are only
pathogens’ resistance
lethal when commechanisms12,13.
bined with mutations in others16. This
The goal of antibiotic development is
is also true for
inhibition of essential
pathogens. We should
enzymes — those the
therefore target gene
pathogen needs to surproducts which are
vive. But survive
essential
together,
where? Traditionally,
even when they are
tests to determine
not essential individwhat enzymes are
ually. For example,
essential have been
M. tuberculosis has
in rich, highly
two genes encodoxygenated culing isocitrate lyase
ture medium. The
enzymes, each of
conditions facing Society’s ongoing struggle against infectious disease. which is capable of
pathogens in the
supporting
lipid
host during many infections — especially metabolism. Disruption of both genes in
those that are persistent — can be drastically combination, but neither alone, causes rapid
different from and more demanding than bacterial decline in vivo(J.McKinney,personal
such conditions in vitro. Not only do meta- communication). Why not target both lyases
bolic niches in vivo differ from culture broth at once? This idea will require fundamental
in many ways (for example, in oxygen, iron, changes in scientific and regulatory
pH and carbon source), but the immune approaches. First, antibiotic development
system acts to suppress the pathogen’s repli- needs to be cooperative, not competitive —
cation and damage many of its molecules. an approach that a not-for-profit drug comSuccessful pathogens adapt by expressing a pany could pursue using drug candidates
different set of genes than they do in from different manufacturers. Second, when a
culture14. Accordingly, a different repertoire successful combination therapy involves a
of genes is essential in vivo than in vitro9,11,15. new unapproved drug, regulatory agencies
In short, essentiality is conditional and the should allow approval of the combination to
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proceed based on clinical tests of the combination itself, rather than insisting on
approval for each individual component as
they do now.
Another premise that handicaps antibiotic
development is that targets in the pathogen
must have no equivalent (homologue) in
the host. This is to avoid harming the host.
Yet most classes of targets inhibited by
antibiotics do have host homologues, except
those involved in cell wall synthesis. It is
time to abandon the premise.Contemporary
structural, computational and chemical
biology should be able to engineer
compounds that can harm the pathogen
without harming the host17.
Conventional antibiotic development
has reached an impasse, partly because it
demands that new agents have broadspectrum activity. This imposes severe limitations, as targets must be widely conserved
across pathogens — and even then only the
most conserved subsites can be targeted.
In contrast, it is medically preferable and
will preserve the utility of the drugs longer,
if antibiotics are highly specific, so that
each one is used less often8.
Treating infections with pathogen-specific
rather than broad-spectrum antibiotics
(whenever possible) will require prior,rapid,
accurate and specific diagnosis. It makes no
sense to use twenty-first century technology
to develop drugs targeted at specific infections whose diagnosis is delayed by nineteenth-century methods. Advances in PCR,
mass spectroscopy, quantum dot-enhanced
immunoassays, nanotechnology, instrumentation and other technologies should be
used to develop diagnostics. With further
investment, doctors could expect to submit
patient specimens (such as throat swabs,
blood or urine) to analysis, and receive diagnoses in many cases within minutes to hours.
Today, diagnosis usually takes a day or more.
Without minimizing the challenge, we
should acknowledge that pretreatment
diagnosis is key to minimizing the use of
broad-spectrum agents and keeping even in
the endless race against drug resistance8.
It is time to start applying new technologies to antibiotic development. Here are
three examples. First, conventional gene disruption in the pathogen does not allow one
to test the role of a gene during a given stage
of infection, such as latency. If disruption of
the gene precludes growth in vitro, then the
gene-deficient mutant cannot be studied at
all9. To determine whether a given target is
essential in vivo we need ‘conditional gene
inactivation’. This allows the investigator to
turn a gene off at a particular time after infection has begun, and thereby model the effect
of treating the infection with an antibiotic
directed against the gene product.
Second, we must not rely exclusively on
screening chemical libraries against enzymes
isolated from the bacteria. Although this
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approach identifies chemical compounds
that inhibit specific targets, it cannot reveal
whether they would affect that target inside
the bacterium, or even if they would get into
the pathogen. We need to identify up front
those compounds that can enter the bacterium and inhibit the target in its natural
setting. For example, we could replace an
endogenous gene encoding a potential target
with a ‘conditional hypomorphic allele’,
allowing reduction but not complete elimination of the target (which could kill it).
Then we could screen chemical libraries to
find compounds to which the ‘weakened’
mutant is particularly sensitive9.
Third, innovative chemistry can allow us
to find more potent inhibitors more quickly
and cheaply. Drug development usually
starts with inhibitors that work at nanomolar
concentrations. Conventional screening of
compounds rarely yields inhibitors active New approaches to screening chemical libraries
below the micromolar range. It can take are needed to develop antibiotics.
teams of chemists months to make
a micromolar inhibitor a
up and running. Each is
thousand-fold more active.
devoted to one or a small
But the target enzyme
number of infectious
itself may be able to
diseases. Their growing
select weakly binding
success22 suggests that
compounds that are
it is possible to
mutually and covainvolve
private
lently reactive from
industry in work
two separate but comthat society needs,
plementary chemical
but the market does
libraries.The enzyme
not
competitively
can then catalyse their
reward.
covalent reaction into a
One model, funded in
single new compound that
substantial part by the Bill
inhibits the enzyme with higher
and Melinda Gates Foundation
affinity18.
and the Rockefeller Foundation,
Finally, we must exploit microbial diver- involves small, not-for-profit drug companies
sity better. Many drug leads have been natur- that are virtual and physically distributed. The
for
Malaria
Venture
al products developed from one bacterial Medicines
order, Actinomycetales19. But most of the (www.mmv.org) takes ideas, hits or leads,
microbial universe remains unexplored, mainly from academic scientists, and uses a
contract mechanism to fund
because most microbial species
medicinal chemistry and pharremain to be cultured. For “It makes no sense to
example, studies of the use twenty-first century macology in the labs of other academics or pharmaceutical
microbes in soil8,19 and water technology to develop
firms21. Similar approaches are
and the viruses that prey on drugs targeted at
20
them could reveal many com- specific infections,
taken by the Global Alliance for
Tuberculosis Drug Development
pounds and enzymes that may whose diagnosis is
(www.tballiance.org) and the
help a given species compete delayed by nineteenthDrugs for Neglected Diseases
with others in its environment. century methods.”
Initiative (www.dndi.org)21.
These natural products can
teach us a great deal about microbial vulnerA second model of public–private
abilities and how to exploit them.
partnerships involves on-site research and
development funded by a major pharmaceuImpossible? Think again
tical company in conjunction with a public
Is it hopelessly unrealistic to imagine partner, such as The Novartis Institute for
not-for-profit drug companies working in a Tropical Diseases. This is funded jointly by
smart regulatory environment, applying Novartis and the Singapore Economic Develfresh scientific approaches to antibiotic opment Board (www.nitd.novartis.com). A
development? Perhaps the most challenging third model, also funded in substantial part
aspect of this three-part vision is the notion by the Gates Foundation, is represented by
of a not-for-profit drug company. Yet, at The Institute for OneWorld Health
least three models of public–private partner- (www.oneworldhealth.org). This agency
ships for development of anti-infectives21 are uses donated intellectual property to operate
a small, on-site, not-for-profit drug company
that prepares vaccines or drugs for malaria,
leishmaniasis, trypanosomiasis, helminth
infections and diarrhoeal diseases. Finally,
the biotechnology industry appears to be
positioning itself to contribute to the
public–private partnership model through
another Gates Foundation-funded initiative, BIO Ventures for Global Health
(www.bvgh.org).
All sectors of society, including the
pharmaceutical industry, have a major stake
in the control of infectious diseases, not only
for medical reasons, but also for global
economic development and security23. It is
in the interest of both rich and poor societies
that initiatives such as those described above
grow by orders of magnitude and broaden
their scope to include all major infectious
diseases that the pharmaceutical industry
does not adequately address.
■
Carl Nathan is in the Department of Microbiology
& Immunology, Weill Cornell Medical College,
and Programs in Immunology and Molecular
Biology, Weill Graduate School of Medical
Sciences of Cornell University, 1300 York
Avenue, New York 10021, USA.
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Acknowledgements
Thanks to A. Apt, K. Deitsch, H. Djaballah, B. Ganem,
W. Jorgensen, T. Kapoor, M. MacCoss, V. Mizrahi, S. Projan,
L. Quadri, K. Rhee, M. Rosenberg, D. Russell, D. Scheinberg,
D. Schnappinger, D. Tan, T. Templeton and P. van Helden for
stimulating discussions. Special thanks are due to P. Davies, S. Ehrt,
M. Glickman, B. Kelly, J. McKinney and S. Nwaka.
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