Download The situation on antimicrobial agents and chemotherapy in 2002

Meeting Highlight
The situation on antimicrobial
agents and chemotherapy in 2002:
Highlights of the 42nd ICAAC
1. Introduction
2. Infectious diseases as a global
health and socio-economic
problem
3. Understanding and overcoming
antibiotic resistance
4. New antimicrobial agents
5. Conclusion and expert opinion
27 – 30 September 2002, San Diego, USA
Carmela Giglione & Thierry Meinnel
Centre National de la Recherche Scientifique, Bâtiment 23, 1 avenue de la Terrasse,
F-91198 Gif-sur-Yvette cedex, France
The 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy took place in San Diego on 27 – 30 September 2002. The meeting
was held in the light of current events. Bioterrorism, malaria, issues of surveillance and multiple resistance were discussed in depth. Few truly new
drugs or potential targets were presented. Peptide deformylase inhibitors
and several other metalloenzymes as new targets were among the most
promising results.
Keywords: bioterrorism, daptamycin, deformylase, horizontal transfer, malaria, quorum-sensing,
resistance
Expert Opin. Ther. Targets (2002) 6(6):691-697
1.
Introduction
Infectious diseases caused by bacteria, fungi and parasites affect hundreds of millions
of people worldwide. In 1996, the World Health Organization (WHO) estimated
that infectious diseases were responsible for the deaths of more than 17 million people every year. Renewed interest in the discovery of new antibiotics has been driven
by the development of resistance to the drugs commonly used against them. The
42nd Interscience Conference on Antimicrobial Agents and Chemotherapy
(ICAAC), organised by the American Society for Microbiology, is the premier international scientific meeting on infectious disease and developments in anti-infective
medicine. More than 12,000 scientists from around the world participated in the
ICAAC to exchange and provide timely information to improve healthcare and the
management of infectious diseases. Full details of the ICAAC programme are available [101,102]. Due to the scope of the meeting, this report will mainly focus on antibacterial agents and therapy.
Infectious diseases as a global health and socio-economic
problem
2.
2.1 Emerging and re-emerging diseases
2.1.1 Emerging pathogens
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The topic of emerging pathogens was partially covered, and various new diseases
were presented, for example, an emerging paediatric infection caused by the raccoon
roundworm, the issue of endemic mycoses as a concern for travellers, and the recent
outbreak of Dengue fever in Hawaii. A recent survey on emerging pathogens has
recently been published [1].
2.1.2 Bioterrorism and re-emerging diseases
Last year, the 41st ICAAC was postponed from its original late-September schedule
until December following the events of 11 September and their consequences. This
2002 © Ashley Publications Ltd ISSN 1472-8222
691
42nd Interscience Conference on Antimicrobial Agents and Chemotherapy
year, the topic of bioterrorism was largely covered in three
dedicated sessions:
• Bioterrorism agents in children.
• Bioterrrorism and the clinical microbiology laboratory.
• The hospital response to bioterrorism.
S Bukofzer (Abbott Laboratories, Atlanta, USA) presented
data on the activity of ABT-492, a new quinolone active
against the anthrax agent Bacillus anthracis. Finally, the
ICAAC gave a special award to AS Fauci, Director of the
National Institute of Allergy and Infectious Diseases (NIAID),
Bethesda, USA. In his plenary lecture entitled ‘Bioterrorism in
the spectrum of emerging and re-emerging diseases’, Fauci
emphasised the differences between bioterrorism and biowarfare, showing how ‘easily’ a homogeneous, healthy population
of young soldiers can be protected in the event of biowarfare,
in comparison to the difficulty of protecting a whole heterogeneous population in the event of bioterrorism. Although
only 22 cases of human disease and five deaths were confirmed after the anthrax attack in late 2001 [2], the chaos experienced during the attacks on the US postal service was of
another order of magnitude. Recent major outbreaks in
B. anthracis toxicity [3] were also acknowledged. According to
Fauci, the US must be prepared for an even worse scenario
than an anthrax attack: a bioterrorism attack with variola
virus, the cause of smallpox disease, which is capable of causing mass civilian casualties. Finally, Fauci also gave details of
how the $1.5 billion budget allocated by the US government
to the National Institutes of Health (NIH) in 2003 to combat
bioterrorism [4] will be spent. This investment in counteracting bioterrorism is 40% of the 16% rise in the total
NIH budget in 2003; 95% of this funding will be given to the
NIAID. Fauci stressed that true results – not only interesting
progress – were to be expected in the short-term. However,
concern about the smallpox threat was recently lowered by:
• Studies indicating that a 10-fold dilution of the 15 million
doses of vaccine currently in the US stockpile did not affect
vaccination potency.
• The donation of 85 million additional doses of vaccine by
Aventis Pharma [4,5].
2.2 Microbial drug resistance
2.2.1 Resistance spreading: the impact
of surveillance
and clinical data
The Aventis Pharmaceutical Award and lecture by F Baquero
(Hospital ramon Y cajal, Madrid, Spain), entitled ‘Microbial evolution under the influence of human chemotherapy’, reviewed
the ability of microbes to adapt to the presence of powerful antimicrobials with extremely complex and specific responses. The
ICAAC therefore opened with a major theme; surveillance.
Many sessions assessed this topic (‘surveillance and early detection of resistance’, new methods for analysis of antimicrobial
resistance surveillance data). From these sessions, it appears that
the use of early surveillance methods to detect emerging resistance, and the determination of resistance mechanisms, are clearly
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vital. For instance, Streptococcus pneumoniae is a key causative
pathogen of community-acquired respiratory tract infections
(CARTIs). Empirical management of CARTIs with β-lactams
and macrolides (particularly erythromycin, clarithromycin and
azithromycin) have spread resistance to these antibiotics at an
alarming rate worldwide. International surveillance programmes
are now aimed at assessing global S. pneumoniae resistance [6]. It
has been concluded that new antimicrobials that are not susceptible to the same mechanism of resistance are required. Telithromycin (a member of a new class of ketolides) and peptide
deformylase inhibitors (see Section 4) were proposed to be two
such compounds.
Some of the social, economic and political factors that contribute to the development of resistance were also raised.
Unsurprisingly, the widespread and most often inappropriate
use of antimicrobials was repeatedly identified as the major
factor driving the development of resistance. The message is
clear: unnecessary antibiotics are harmful and are not always
the answer to disease. In an interesting session on this subject
entitled ‘Antibiotic use in food animals: impact on resistance
in humans’, H Goossens (University Hospital Antwerp,
Edegem, Belgium) discussed the current knowledge of antimicrobial use (and misuse) in humans and animals and
revealed the difficulty of evaluating it. Data from different
countries are difficult to compare because of the use of different units of measurement. A slight decrease in overall antibiotic production has occurred in the past 2 years. The
problems in the developing world were discussed, and the situation in various countries was compared. For instance, in the
US, 85% of antibiotic use is for animal prophylaxis, compared to only 9% for human treatment. In Europe, the recent
noticeable effort to ban the use of antibiotics as animal
growth promoters has resulted in a reversal of this trend; 60%
of antibiotics are now used for humans in the European Community. This topic was analysed more deeply by HC Wegener
(Danish Zoonosis, Copenhagen, Denmark). On the other
hand, France, Spain and the US clearly show the most excessive use of antibiotics in human therapeutics, whereas in The
Netherlands, a very low usage was acknowledged. However,
the data are collected at the outset, i.e., how much is sold to
users. The Copenhagen recommendations state that every
member of the European Community should be able to collect data. It is generally agreed that in order to optimise antibiotic use, individuals should not only know what is being
used, but also how it is being used. Thus, questions were
posed to see how much was really used. Answers were that as
few as 30 – 36% of the total amount of antibiotics bought by
the consumers could be used in some countries, with people
making stocks that will never be consumed. This makes interpretations about the current use of antibiotics a big issue,
given that the occurrence of antibiotic overuse depends on
social habits and customs.
P Trieu-Cuot (Laboratory Pasteur-Necker, Paris, France)
reviewed the mechanisms of transfer of resistance by horizontal gene transfer (conjugative plasmids and transposons,
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transduction and tranformation). Trieu-Cuot also analysed
the direction of the gene flux, showing that it is generally
from low GC% Gram-positive bacteria (Bacilli, Streptococci
and Staphylococci) towards GC% Gram-positive (actinobacteria) and Gram-negative bacteria. This may be due to the fact
that the transcription promoters and ribosome-binding sites
of low GC% Gram-positive bacteria work well in other systems, whereas the reverse is usually untrue. The most efficient
donor was found to be Enterococcus faecalis. Finally, although
rather obvious, it was worth stressing the impact of sharing
the same ecosystem (e.g., digestive tract) when dealing with
transfer between distantly-related bacteria. On this subject,
the well-documented talk by A Andremont (Groupe Hospital, Bichat-Claude Bernard, Paris, France) proposed a role of
the commensal flora in the spread of resistance. The diversity
and number of flora (1014) is much higher than that of pathogenic bacteria (108-10) at the site of infection. It was also suggested that the concentration of the antibiotic in the
commensal flora is sometimes below the MIC (minimum
inhibitory concentration). The audience asked how to solve
this problem and how to design a drug with the least impact.
It was proposed that manipulation of pharmacokinetics and
pharmacodymanics and assessing drugs in terms of ecological
impact could be one solution. However, it was not mentioned
as to whether the development of drugs that inhibit bacterial
pathogenicity but not growth was realistic.
Due to the fact that it is antagonistic to the beneficial
effect of antibiotics, it is clear that this important issue raised
by Andremont will not be easily overcome. Again, restricting
the use of such drugs to when they really are necessary is currently the only way to diminish the selection for resistance.
The impact of animal antibiotic use on the emergence of
resistance in human commensal flora [7] is a priori one of the
most pressing concerns.
2.2.2 Multiple antibiotic
resistance
Staphylococcus aureus has been known for years to respond to
antibiotics with a variety of resistance mechanisms. It rapidly
evolved to resist β-lactams, such as penicillin, in as early as the
1940s, before challenging methicillin in the 1960s. The structural basis for β-lactam resistance is now known since
3D models of the penicillin-binding protein-2a complexed
with penicillin and methicillin are now available [8]. Vancomycin, a glycopeptide that also targets the cell wall, has been
the mainstay of treatment for methicillin-resistant S. aureus
(MRSA) for the past 20 years. Strains of MRSA with intermediate susceptibility to vancomycin (VISA) were first identified
in Japan in 1996, and have now been identified around the
world. Vancomycin-resistant enterococci (VRE) were first
identified in the late 1980s and became widespread in the
US in the early 1990s. Since the transmission of vancomycin
resistance from VRE to Staphylococcus was accomplished in
the laboratory a decade ago [9], the fear that vancomycin-resistant S. aureus (VRSA) would soon appear has been in
the minds of all epidemiologist experts.
The 42nd ICAAC was held in the context of the most recent
report in June 2002 describing the first documented case of
infection by a VRSA strain in a patient in the US [10]. The isolate contained the VanA-resistance gene from enterococci.
However, this S. aureus isolate proved sensitive to a number of
other drugs, including trimethoprim-sulfomethoxasole and linezolid. It is only a matter of time before S. aureus strains resistant to all known antibiotics are identified. A slide session was
dedicated to multiple antibiotic resistance in S. aureus
(MARSA). Its scope was to assess the genetic basis of glycopeptide and fusaric acid resistance. AJ O’Neill (University of Leeds,
Leeds, UK) reported that fusaric acid resistance was acquired in
S. aureus by horizontal transfer of a plasmid-endoded fusB gene.
Understanding and overcoming antibiotic
resistance
3.
As genetic information exchange between even distantly-related
bacteria is known to be possible [11], the above data on VRSA
and MARSA demonstrate the immediate need for a better characterisation and understanding of resistance mechanisms.
3.1 Antibiotic
exporters and their control
The issue of broad specificity multi-drug resistance efflux
pumps (MDRs) and the effect of pump function on antimicrobial susceptibility was covered in several sessions. Almost
all bacteria have such pumps encoded on their own chromosome, the expression of which is fine-tuned [12]. The various
mechanisms of regulation of MDR expression were reviewed
by H Nikaido (University of California, Berkeley, USA).
Induction of MDR gene expression occurs by a variety of distinct mechanisms involving two components; repressorinducer or quorum-sensing systems. The global expression of
MDRs in Pseudomonas aeruginosa was presented by DG Storey (University of Calgary, Calgary, Canada). L Cao (Queen's
University, Kingston, Canada) reported a novel P. aeruginosa
gene encoding a repressor of an operon of unknown function
responsible for MDRs. A full description of regulatory mechanisms, but also of new efflux pumps, is critical. J Huang
(GlaxoSmithKline, Collegeville, USA) was given a special
award at the 42nd ICAAC in recognition of a novel approach
to this issue. Based on the knowledge of the importance of
induction in MDRs and using the 1700 open reading frame
expression library of S. aureus, together with a simple reverse
genetic screen, he isolated a novel proton-driven efflux pump
(MdeA). Hence, overexpression of MdeA conferred resistance
to a number of antibiotics, such as novobiocin and fusidic
acid. Spontaneous S. aureus mutants with mutations in the
MdeA promoters causing overexpression of the gene could be
isolated. The fact that the mutations were shown to confer
resistance to the same substrates shows the relevance of this
approach. Finally, it was noted that efflux pump inhibitors
would be valuable tools in combating resistance (A Lee,
Essential Therapeutics, Mountain View, USA; V Moudgal,
Wayne State University School of Medicine, Detroit, USA).
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42nd Interscience Conference on Antimicrobial Agents and Chemotherapy
3.2 Overcoming resistance to antibiotics targeting the
cell wall
Most major enzymes in peptidoglycan biosynthesis – transglycosylases and transpeptidases – have now been identified,
and several antibiotics such as moenomycine, teicoplanin,
vancomycin and β-lactams are already known to target this
process. Although the cell wall is a large source of antibacterial
agents [13], their extensive use in the past 15 years has led to
the development of resistance.
D Kahne (Princeton University, Princeton, USA) reported
that the glycopeptide, vancomycin, inhibits cell wall formation by binding to the D-Ala-D-Ala C-terminal dipeptide of
the peptidoglycan precursor, therefore blocking a transpeptidation step. Resistance to vancomycin is derived from the
ability of the cell to reprogramme its machinery, allowing the
synthesis of a precursor with low affinity to the drug. There
are two types of resistance to consider. In the first mechanism, a cluster of genes is activated as a result of the
two-component system (VanR–VanS) involving a kinase and
a sensor. Hence, when activated by vancomycin, the
VanA cluster of seven genes found on the transposable transposon, Tn1546, allows the incorporation of D-Ala-D-Lactate
instead of the above D-Ala-D-Ala dipeptide. This drives vancomycin resistance. Teicoplanin, a structural analogue of vancomycin, is inactive against VanA resistance but active against
VanB resistance, which has a similar mechanism of action.
Kahne presented vancomycin derivatives with a hydrophobic
substituent on the carbohydrate moiety, which block the
transglycolase step of peptidoglycan synthesis. These molecules were able to overcome vancomycin resistance in VRSA
or VRE. Kahne finally stressed the importance of learning
more about the mechanism of action of vancomycin and its
derivatives in order to design better antibiotics. JL Pace
(Theravance Inc., San Francisco, USA) presented one of the
most promising molecules of the meeting, a semisynthetic
substituted glycopeptide named TD-6424.
Like vancomycin, daptomycin, a novel lipopeptide antibiotic, has broad activity against Gram-positive bacteria. Interestingly, it has a different mode of action, which makes it a
potential candidate for the treatment of VRE and VRSA.
J Silverman (Cubist Pharmaceuticals Inc., Lexington, USA)
summarised the mode of action and mechanism of daptomycin resistance. This antibiotic forms ion-conducting structures that allow efflux of cytoplasmic ions such as potassium.
Reduced binding of daptomycin appears important for
resistance mechanisms. At the ICAAC this year, daptomycin,
which is currently undergoing Phase II and III clinical trials,
was the subject of a number of poster presentations aimed at
assessing its activity in vivo. Ornithine derivatives of daptomycin were presented by Cubist Pharmaceuticals.
The modes of action of two glycopeptides, oritavancin
(JS Loutit, InterMune Pharmaceuticals, Brisbane, USA) and
ramoplanin (S Walker, Princeton University, Princeton,
USA), were also presented. Both of these compounds inhibit
late-stage biosynthesis of the cell wall. Ramoplanin was
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proposed to inhibit the transglycosylation step of peptidoglycan synthesis and to bind to lipid II in preference to lipid I.
Ramoplanin, now in Phase III clinical studies, is investigated
for the prevention of bloodstream infections caused by VRE.
4.
New antimicrobial agents
Novel drugs, preferably blocking new targets, are desperately
needed in the short-term to avoid resistance. This requirement was addressed in a series of interesting sessions. As
usual, these were the most highly attended sessions of the
ICAAC meeting, and they all attracted thousands of attendants. New glycopeptides, fluoroquinolone, oxazolidinone and
DHFR (dihydrofolate reductase) inhibitors were presented.
A Lewendon (PantTherix Ltd, Glasgow, UK) proposed that
chorismate synthase, the seventh enzyme of the shikimic acid
biosynthetic pathway of bacteria, plants and fungi that is
absent in mammals, could constitute a novel target for antimicrobial chemotherapy.
Over the last 2 years, at the 40th and 41st ICAAC, British
Biotech Ltd (Oxford, UK) and Versicor Inc. (Fremont, USA)
reported impressive progress of peptide deformylase (PDF)
inhibitors, with one lead component called BB-83698 being
most promising [14]. Research and preclinical studies on PDF
inhibitors have shown high potency against bacteria causing
pneumonia and other serious infections, including strains resistant to current antibiotics. This year, PDF was once again identified as a most promising target for new generation antibiotics.
4.1 Peptide deformylase inhibitors:
the next class of
antibiotics?
Newly synthesised bacterial proteins are tagged with a
one-carbon unit called a formyl group, which is later cleaved
by PDF, an essential enzyme. T Meinnel (Centre National de
la Recherche Scientifique, Gif-sur-Yvette, France) reviewed
why PDF is well-suited for target-based screening of new antimicrobials. The biology and structural and chemical characterisation of PDF make it therefore a most attractive target
[15,16]. The rational and chemical basis of PDF inhibition was
discussed by D Pei (Ohio State University, Columbus, USA).
British Biotech and external investigators contributed seven
posters on related compounds at the 42nd ICAAC. These
posters [103] described the in vivo and in vitro activities of
BB-83698 and other potent PDF inhibitors against a variety
of respiratory tract and other infections, and the results of
experiments investigating bacterial resistance to PDF inhibitors compared with antibiotics currently in use. On 1 October
2002, British Biotech and GeneSoft Pharmaceuticals
announced the start of human trials for BB-83698.
This year, the most spectacular progress on PDF was presented by Versicor. Out of the 24 presentation contributions
by this company, seven posters and two oral presentations
dealt with PDF inhibitors. Versicor’s novel oral PDF inhibitor, VRC-4887, was shown to be effective in preclinical studies against serious upper respiratory pathogens, including
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S. pneumoniae, Moraxella catarrhalis, Enterococcus spp. and
Haemophilus influenzae, including drug-resistant strains. Like
BB-83698, VRC-4887 belongs to a new antibiotic class for
the CARTIs market. Versicor is developing PDF inhibitors in
collaboration with Novartis. Z Yuan (Versicor, Fremont,
USA) summarised several studies of PDF inhibitors, including VRC-4887, during his presentation entitled ‘Discovery,
SAR [structure–activity relationships] and preclinical activities of bacterial deformylase inhibitors’ at the ‘New antimicrobial agents’ poster summary session. J Trias (Versicor,
Fremont, USA) discussed the future of this exciting new class
based on its unique properties and knowledge to date in a talk
entitled ‘PDF inhibitors: the next class of antibiotics?’ In vivo
active molecules from Versicor’s programme will enter clinical
trials in 2003. The issue of resistance was raised several times.
Apparently, resistance rate depends on the bacterial type and
involves the PDF itself or the transformylase [17]. Whether or
not MDR genes can be induced was not discussed, although
efflux from acrAB-tolC is a major cause of resistance to PDF
inhibitors in many Gram-negative bacteria.
4.2 Will mechanism-based drug design provide a new
class of antibiotics?
Bacterial metalloenzymes are attractive targets for mechanismbased antibiotic discovery, and are an underexploited source
of drugs. Growing scientific interest in metalloenzymes as
novel targets for antibiotic therapy was reflected at the 42nd
ICAAC in a dedicated session. J Clements (British Biotech
Pharmaceuticals Ltd, Oxford, UK) reported that several metalloenzymes, including PDF, have been found to be essential
for bacterial survival. The example of urease, a nickel enzyme,
was discussed. Another interesting target is encoded by LpxC,
a zinc deacetylase involved in lipid A biosynthesis. Lipid A,
which forms the hydrophobic anchor of lipopolysaccharide, is
required for bacterial growth and virulence. Versicor presented VRC-5264, a new inhibitor of LpxC. Clements also
noted that inhibitors against anthrax lethal toxin and botulinum toxin, two metalloenzymes, could be important in biodefence programmes. Meinnel proposed Type I methionine
aminopeptidase, an enzyme belonging to N-terminal protein
maturation, as a novel target. Finally, J Toney (Margaret and
Herman Sokol, Upper Montclair, USA) reviewed the topic of
metallo β-lactamase (MBL) inhibitors. MBL belongs to the
four classes of β-lactamases [18] and has the broadest substrate
profile of all β-lactamases [19]. MBL can hydrolyse a variety of
substrates including carbepenems, penicillin and cephalosporin members of the β-lactam class, rendering them ineffective as antibiotics. Toney reported that most inhibitors
interact with the binuclear zinc core of the active site.
5.
Conclusion and expert opinion
5.1 New drugs
in the pipeline?
What about new antibacterial compounds? Unfortunately,
few new compounds or targets were presented in San Diego.
Daptomycin, ramoplanin, TD-6424 and vancomycin derivatives look promising but clarification of their targets is
required. This is generally true for most compounds targeting
the cell wall. Before the meeting was held, no antibacterial
drug identified by target-based screening had advanced into
clinical trials. This has led some pharmaceutical researchers
to the conclusion that the majority of the novel targets are
not ‘druggable’. For instance, most major companies started
programmes on PDF years ago, and characterised PDF inhibitors. Such molecules are now successfully being developed by
emerging companies such as Versicor and British Biotech.
These molecules are presently the most exciting antibacterial
compounds being investigated as they could be the first molecules identified by target-based screening. However, it is a
shame that the chemical nature of BB-83698 and VRC-4887
was not revealed at the meeting. Members of the ICAAC programme committee stressed that the chemical structures of all
molecules presented at the next ICAAC should be available.
Finally, it was surprising that the LuxS quorum-sensing protein was not discussed in the session dedicated to metalloenzymes. The LuxS protein has a catalytic metal site
coordinated by two histidines and a cysteine [20], similar to
PDF. The clear link between quorum-sensing and virulence,
as well as its involvement in MDR induction
(see Section 3.1), suggests that quorum-sensing mechanisms
could be used as novel drug targets [21].
5.2 Malaria
Among the many sessions dedicated to non-bacterial infections (HIV, hepatitis B, fungi, worms etc.), the session on
malaria was of particular interest this year. The two main
drugs currently in use, chloroquine and sulfadoxine/
pyrimethanine, are no longer effective because of the development of increased resistance. The discovery of new targets
and new drugs is required to cure acute, uncomplicated
forms of the disease. The 42nd ICAAC was held in the context of the release of the genomes of Plasmodium falciparum
(the apicomplexan protist responsible for the disease) and its
vector, the mosquito Anopheles gambiae, in two special issues
of Nature and Science, respectively. What will be the immediate impact of this work on antimalaria therapy? Although
this is unclear in the case of the mosquito, the analysis of the
P. falciparum genome shows some interesting trends [22]. For
instance, 12% of the proteome codes for the apicoplast, an
organelle that resembles a chloroplast but is devoid of photosynthetic ability. This essential organelle, discovered in
1997, is already the target of many antimalarial drugs and is
now the object of intense interest. Surprisingly, the apicoplast as a source of novel targets was almost absent from the
San Diego meeting. Nevertheless, two such targets, chorismate synthase and PDF, which were both stressed to be
excellent targets for new antibacterial agents (see Section 4)
were discussed. The proteins from bacteria and malaria parasite are very similar. Thus, it was suggested that the bacterial
PDF inhibitors already available should also be very effective
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against malaria [23]. This is also the case for fosmidomycin,
an inhibitor of the mevalonate-independent isoprenoid
pathway of the parasite apicoplast, a drug which has already
been evaluated for its antibacterial activity in the 1980s.
Interestingly, fosmidomycin, a phosphonate derivative,
resembles a metalloenzyme inhibitor.
Will such broad spectrum drugs ever be used to fight
malaria? Unfortunately, this is very unlikely due to the spread
of resistance and economical considerations. Hence, treatment
of large populations suffering from malaria will unavoidably
lead to acquisition of resistance by commensal flora bacteria
(see Section 2.2.1) making the new target rapidly unusable for
antibacterial therapy. A reduced market targeting a rich population appears more likely to transform the huge investments
of pharmaceutical companies required to support the development of a new drug into secured, long-term profits. Thus,
malaria control is still experiencing disinterest from pharmaceutical companies, not only because of the absence of an economical ‘market’, as has sadly often been pointed out, but also
because of the risk of resistance associated with general treatment of a disease that currently affects half a billion people.
Hopefully, the strong involvement of WHO in support of
malaria research will be helpful in combating the disease [24].
1.
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Surprisingly, the recent impact of genomics on anti-infective
drug discovery [25] was represented in only a few communications in San Diego. Although the application of genomics has
not yet led to the identification of novel antibacterial agents,
it still remains a powerful tool for drug discovery [26]. The
strategy presented by J Huang to identify new MDR genes in
S. aureus must be acknowledged in this respect. Similarly, the
approach of B Hutter (GPC Biotech AG, Martinsried/
Munich, Germany) should be mentioned. In this study, a
whole genome DNA array of Bacillus subtilis was generated,
and gene expression patterns induced by 37 compounds were
investigated using a profiling platform. From this, six different modes of action were reported. For instance, puromycin,
an inhibitor of translation, was shown to induce heat shock
genes such as the chaperones GroES, GroEL and DnaK. This
is not a surprising result as unfolded proteins are generated by
puromycin. Clearly, the method described by Hutter is a valuable tool for the study of antibacterial compounds at various
stages of development. Finally, the potential of structural proteomics [27] in drug discovery was not perceivable at the
ICAAC meeting. However, in the case of PDF inhibitors, it is
clear that such an approach is of great value [28].
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A recent review of PDF and its use as a
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Websites
101. http://www.icaac.org
The official website of the ICAAC.
102. http://www.sound-solution.com
The website to access to purchase a
CD-ROM containing audiotapes of the
majority of the ICAAC sessions of the 42nd
ICAAC in .mp3 format ($200).
103. http://www.britbio.co.uk/icaac2002.htm
The website to access to obtain a free
electronic version of the posters presented by
British-Biotech at the ICAAC in .pdf format.
Affiliation
Carmela Giglione PhD & Thierry Meinnel PhD†
†Author for correspondence
Centre National de la Recherche Scientifique,
Bâtiment 23, 1 avenue de la Terrasse,
F-91198 Gif-sur-Yvette cedex, France
Tel: +33 1 6982 3612; Fax: +33 1 6982 3607;
E-mail: [email protected]
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