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Antimicrobials
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Antimicrobials Antimicrobials: time to act! Editorial overview Patrice Courvalin and Julian Davies Current Opinion in Microbiology 2003, 6:425–426 This review comes from a themed issue on Antimicrobials Edited by Patrice Courvalin and Julian Davies 1369-5274/$ – see front matter ß 2003 Elsevier Ltd. All rights reserved. DOI 10.1016/j.mib.2003.09.012
Patrice Courvalin Unite´ des Agents Antibacte´riens, Institut Pasteur, 25-28, rue du Docteur Roux, 75724 Paris cedex 15, France e-mail: [email protected]
Patrice Courvalin M.D., is a Professor at the Institut Pasteur where he directs the French National Reference Center for Antibiotics and is the Head of the Antibacterial Agents Unit. He is an expert in the genetics and biochemistry of antibiotic resistance. His research has led to a revision of the dogma describing natural dissemination of antibiotic resistance genes. He has demonstrated that a wide variety of pathogenic bacteria can promiscuously exchange the genetic material conferring antibiotic resistance, proved that conjugation could account for dissemination of resistance determinants between phylogenetically remote bacterial genera, elucidated the transposition mechanism of conjugative transposons from Gram-positive cocci, and most recently, has obtained direct gene transfer from bacteria to mammalian cells.
Julian Davies Dept of Microbiology and Immunology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada e-mail: [email protected]
Julian Davies is Professor Emeritus of Microbiology and Immunology at UBC and holds an executive position at Cubist Pharmaceuticals. He has been interested in antibiotics and antibiotic resistance for some time and maintains an active academic research program, which focuses on several aspects of small molecule biology. He is also a member of the GenomeBC-funded team studying the functional genomics of Rhodococcus RHA1. www.current-opinion.com
In some respects, we live in a strange period of medical history. On the one hand, infectious diseases are still a major scourge of human life, both in the developing world (due mainly to economic and socio-political reasons) and in the industrial world (due to emerging infectious diseases and the appallingly high level of antibiotic resistance). On the other hand, the pharmaceutical industry sees fit to reduce its efforts to find new antibiotics, (in part due to the fact that manifestations such as baldness or inadequate sexual performance have become chronic diseases that require drug therapy). The initial article by Projan analyses this dichotomy from within and comes up with the conclusion that the situation is entrenched, that solutions are available, and that action is required. In the Second World War, with the discovery of benzyl penicillin, the allied governments saw the need and the solution and rallied the young pharmaceutical industry to provide antibiotics as part of the war effort. Perhaps we are coming to a similar crisis, which can be solved by the insistence of the public and the medical profession forcing government to play a more decisive role in convincing industry to step-up the search for new antibiotics. The pharmaceutical industry invested a billion dollars in the ‘make-it-richquick’ technology of high throughput screening and combinatorial chemistry with the expectation that many new targets and antibiotics would be found and transform the drug discovery process. As everyone knows, this expensive gamble failed. In retrospect this was not surprising; how can one find antibiotics by screening large collections of biologically inactive molecules in cell-free reactions? However, as Silver points out in her review of inhibitors of cell wall synthesis, all is not lost and, in retrospect, there remains great potential in target discovery carried out with respect to microbiology and fundamental scientific principles. Bacterial peptidoglycan structures have long been recognised as potential antibiotic targets and good biochemistry and (truly) intelligent screening may still provide the desired magic bullets. Antibiotic use is not restricted to humans: since the 1960s, more antibiotic production has gone into animals for the commercial production of beef and poultry, etc. Early on, pioneers such as Anderson and Datta, and others pointed out the dangers of antibiotic profligacy with respect to the development of antibiotic resistance and the worst happened. There is now convincing evidence for a causal relationship between antibiotic use in animals and the development of antibiotic-resistance in human pathogens. For the glycopeptides vancomycin and avoparcin the case for a role of animal Current Opinion in Microbiology 2003, 6:425–426
426 Antimicrobials
antibiotic use in the creation of a major antibiotic-resistant pathogen in humans (VRE) has been convincingly made. Wegener shows that reducing the antibiotic load in animal feed can reverse this trend and European countries have taken the lead in restricting the use of antibiotics in animals. This policy has proven successful, but there are other countries that are reluctant to take the same action. In the US and Canada, a dozen or more antibiotics are approved for non-therapeutic use (i.e. growth promotion) and despite the active campaigning of groups such as APUA (alliance for the prudent use of antibiotics), the matter is still only at the early stage of government ‘consideration’. This, in spite of the fact that the use of antibiotics in animals directly impacts the treatment of human disease, as has been shown for fluoroquinolone resistance in Campylobacter jejuni, is true for other foodborne diseases. There is much hand-wringing over the problem of antibiotic resistance as various groups search for solutions; Wegener clearly indicates an obvious and simple approach — reduce the use of antibiotics! Continuing with the theme of antibiotic resistance, one of the principal evasive mechanisms employed by microbes is antibiotic exclusion through multidrug efflux pumps. It is likely that this mechanism is universal and is certainly associated, to some extent, with resistance to all antibiotics since their initial use. Some bacteria are predicted (from their genome sequence) to have more than 50 multidrug efflux systems. Clearly such efflux systems for antibiotics evolved from transporters for other substrates. Paulsen provides timely information on the diversity of export functions in bacteria and the ways in which they are regulated. To many biologists, the phenomenon of stable antibiotic resistance is an anomaly as mutations to resistance usually lead to loss of fitness. However, as Andersson describes, the wily microbes have found ways to circumvent this problem through the acquisition of accessory mutations that compensate for the fitness cost leading to stable resistance. The near-universality of hypermutable pathogens in infectious situations, probably occurring as responses to physiological and antibiotic stress, ensures that mutation to antibiotic resistance and compensation occurs hand-in-hand. Interestingly, restoration of fitness mutations has many different phenotypes, some of which may favour survival in the host. The result is that reduction in antibiotic use does not lead to complete loss of resistant strains in any environment. This is significant with respect to the article by Wegener; not only must antibiotic use be discontinued but the same (or structurally-related) antibiotics cannot be re-introduced. As was indicated in Projan and Silvers’ expositions, we must have new antibiotics!
Current Opinion in Microbiology 2003, 6:425–426
Horizontal gene transfer is the major mechanism of the acquisition and dissemination of antibiotic resistance genes. Such exchanges occur between many different genera in mixed bacterial populations and appear to not recognise ‘traditional’ boundaries (for example, between Gram-positive and Gram-negative bacteria). The most important environments for such exchange are the gastrointestinal (GI) tracts of humans and animals; the review by Vedantam and Hecht discusses the microbiology of human gut flora and the major, but often not recognised, roles of anaerobes in gut function, infection and antibiotic resistance. If truth be known, the gut is a veritable microbial bordello, with a very high capacity for horizontal gene transfer, involving many different kinds of mobile genetic elements. Studies of bacterial populations of the GI tracts of animals obviously deserve comparable attention with respect to antibiotic resistance development, especially given the quantities of antibiotics used as growth promotants. In discussion of the ways to overcome the increasing burden of antibiotic resistant pathogens, novel antibiotics are only one of the potential solutions. High on the list of alternatives of treatments for microbial infections, both antibiotic-sensitive and –resistant, are vaccines and other means to stimulate the host immune response. These topics are reviewed by Moingeon et al., and by Dittmer and Olbrich, respectively. Unfortunately, as indicated by Moingeon et al. the success rate for the discovery of effective antibacterial vaccines has been limited. However, these authors describe progress in the development of immunotherapies for a variety of chronic viral diseases and indicate prospects for future success. A related and possibly complementing approach is that of employing bacterial DNA carrying CpG motifs as a means to stimulate the immune system. This is a relatively new approach to infectious disease treatment but good results have been obtained in bacterial, parasitic and viral models. In conclusion, it is clear that infectious diseases still present major medical and scientific problems. The ability of microbes to take evasive action against any established form of treatment has been proved time and time again. To be successful in the future, the concept of antimicrobials has to be expanded. Mere antibiotics are no longer enough to counter the burden of infectious diseases worldwide. The challenges can only be met with increased focus on understanding the fundamental biology of host–microbe interactions; success in providing new therapies will be dependent on full industry, academic and clinical collaborations to an extent that has not yet been realised.
www.current-opinion.com
Antimicrobials Antimicrobials: time to act! Editorial overview Patrice Courvalin and Julian Davies Current Opinion in Microbiology 2003, 6:425–426 This review comes from a themed issue on Antimicrobials Edited by Patrice Courvalin and Julian Davies 1369-5274/$ – see front matter ß 2003 Elsevier Ltd. All rights reserved. DOI 10.1016/j.mib.2003.09.012
Patrice Courvalin Unite´ des Agents Antibacte´riens, Institut Pasteur, 25-28, rue du Docteur Roux, 75724 Paris cedex 15, France e-mail: [email protected]
Patrice Courvalin M.D., is a Professor at the Institut Pasteur where he directs the French National Reference Center for Antibiotics and is the Head of the Antibacterial Agents Unit. He is an expert in the genetics and biochemistry of antibiotic resistance. His research has led to a revision of the dogma describing natural dissemination of antibiotic resistance genes. He has demonstrated that a wide variety of pathogenic bacteria can promiscuously exchange the genetic material conferring antibiotic resistance, proved that conjugation could account for dissemination of resistance determinants between phylogenetically remote bacterial genera, elucidated the transposition mechanism of conjugative transposons from Gram-positive cocci, and most recently, has obtained direct gene transfer from bacteria to mammalian cells.
Julian Davies Dept of Microbiology and Immunology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada e-mail: [email protected]
Julian Davies is Professor Emeritus of Microbiology and Immunology at UBC and holds an executive position at Cubist Pharmaceuticals. He has been interested in antibiotics and antibiotic resistance for some time and maintains an active academic research program, which focuses on several aspects of small molecule biology. He is also a member of the GenomeBC-funded team studying the functional genomics of Rhodococcus RHA1. www.current-opinion.com
In some respects, we live in a strange period of medical history. On the one hand, infectious diseases are still a major scourge of human life, both in the developing world (due mainly to economic and socio-political reasons) and in the industrial world (due to emerging infectious diseases and the appallingly high level of antibiotic resistance). On the other hand, the pharmaceutical industry sees fit to reduce its efforts to find new antibiotics, (in part due to the fact that manifestations such as baldness or inadequate sexual performance have become chronic diseases that require drug therapy). The initial article by Projan analyses this dichotomy from within and comes up with the conclusion that the situation is entrenched, that solutions are available, and that action is required. In the Second World War, with the discovery of benzyl penicillin, the allied governments saw the need and the solution and rallied the young pharmaceutical industry to provide antibiotics as part of the war effort. Perhaps we are coming to a similar crisis, which can be solved by the insistence of the public and the medical profession forcing government to play a more decisive role in convincing industry to step-up the search for new antibiotics. The pharmaceutical industry invested a billion dollars in the ‘make-it-richquick’ technology of high throughput screening and combinatorial chemistry with the expectation that many new targets and antibiotics would be found and transform the drug discovery process. As everyone knows, this expensive gamble failed. In retrospect this was not surprising; how can one find antibiotics by screening large collections of biologically inactive molecules in cell-free reactions? However, as Silver points out in her review of inhibitors of cell wall synthesis, all is not lost and, in retrospect, there remains great potential in target discovery carried out with respect to microbiology and fundamental scientific principles. Bacterial peptidoglycan structures have long been recognised as potential antibiotic targets and good biochemistry and (truly) intelligent screening may still provide the desired magic bullets. Antibiotic use is not restricted to humans: since the 1960s, more antibiotic production has gone into animals for the commercial production of beef and poultry, etc. Early on, pioneers such as Anderson and Datta, and others pointed out the dangers of antibiotic profligacy with respect to the development of antibiotic resistance and the worst happened. There is now convincing evidence for a causal relationship between antibiotic use in animals and the development of antibiotic-resistance in human pathogens. For the glycopeptides vancomycin and avoparcin the case for a role of animal Current Opinion in Microbiology 2003, 6:425–426
426 Antimicrobials
antibiotic use in the creation of a major antibiotic-resistant pathogen in humans (VRE) has been convincingly made. Wegener shows that reducing the antibiotic load in animal feed can reverse this trend and European countries have taken the lead in restricting the use of antibiotics in animals. This policy has proven successful, but there are other countries that are reluctant to take the same action. In the US and Canada, a dozen or more antibiotics are approved for non-therapeutic use (i.e. growth promotion) and despite the active campaigning of groups such as APUA (alliance for the prudent use of antibiotics), the matter is still only at the early stage of government ‘consideration’. This, in spite of the fact that the use of antibiotics in animals directly impacts the treatment of human disease, as has been shown for fluoroquinolone resistance in Campylobacter jejuni, is true for other foodborne diseases. There is much hand-wringing over the problem of antibiotic resistance as various groups search for solutions; Wegener clearly indicates an obvious and simple approach — reduce the use of antibiotics! Continuing with the theme of antibiotic resistance, one of the principal evasive mechanisms employed by microbes is antibiotic exclusion through multidrug efflux pumps. It is likely that this mechanism is universal and is certainly associated, to some extent, with resistance to all antibiotics since their initial use. Some bacteria are predicted (from their genome sequence) to have more than 50 multidrug efflux systems. Clearly such efflux systems for antibiotics evolved from transporters for other substrates. Paulsen provides timely information on the diversity of export functions in bacteria and the ways in which they are regulated. To many biologists, the phenomenon of stable antibiotic resistance is an anomaly as mutations to resistance usually lead to loss of fitness. However, as Andersson describes, the wily microbes have found ways to circumvent this problem through the acquisition of accessory mutations that compensate for the fitness cost leading to stable resistance. The near-universality of hypermutable pathogens in infectious situations, probably occurring as responses to physiological and antibiotic stress, ensures that mutation to antibiotic resistance and compensation occurs hand-in-hand. Interestingly, restoration of fitness mutations has many different phenotypes, some of which may favour survival in the host. The result is that reduction in antibiotic use does not lead to complete loss of resistant strains in any environment. This is significant with respect to the article by Wegener; not only must antibiotic use be discontinued but the same (or structurally-related) antibiotics cannot be re-introduced. As was indicated in Projan and Silvers’ expositions, we must have new antibiotics!
Current Opinion in Microbiology 2003, 6:425–426
Horizontal gene transfer is the major mechanism of the acquisition and dissemination of antibiotic resistance genes. Such exchanges occur between many different genera in mixed bacterial populations and appear to not recognise ‘traditional’ boundaries (for example, between Gram-positive and Gram-negative bacteria). The most important environments for such exchange are the gastrointestinal (GI) tracts of humans and animals; the review by Vedantam and Hecht discusses the microbiology of human gut flora and the major, but often not recognised, roles of anaerobes in gut function, infection and antibiotic resistance. If truth be known, the gut is a veritable microbial bordello, with a very high capacity for horizontal gene transfer, involving many different kinds of mobile genetic elements. Studies of bacterial populations of the GI tracts of animals obviously deserve comparable attention with respect to antibiotic resistance development, especially given the quantities of antibiotics used as growth promotants. In discussion of the ways to overcome the increasing burden of antibiotic resistant pathogens, novel antibiotics are only one of the potential solutions. High on the list of alternatives of treatments for microbial infections, both antibiotic-sensitive and –resistant, are vaccines and other means to stimulate the host immune response. These topics are reviewed by Moingeon et al., and by Dittmer and Olbrich, respectively. Unfortunately, as indicated by Moingeon et al. the success rate for the discovery of effective antibacterial vaccines has been limited. However, these authors describe progress in the development of immunotherapies for a variety of chronic viral diseases and indicate prospects for future success. A related and possibly complementing approach is that of employing bacterial DNA carrying CpG motifs as a means to stimulate the immune system. This is a relatively new approach to infectious disease treatment but good results have been obtained in bacterial, parasitic and viral models. In conclusion, it is clear that infectious diseases still present major medical and scientific problems. The ability of microbes to take evasive action against any established form of treatment has been proved time and time again. To be successful in the future, the concept of antimicrobials has to be expanded. Mere antibiotics are no longer enough to counter the burden of infectious diseases worldwide. The challenges can only be met with increased focus on understanding the fundamental biology of host–microbe interactions; success in providing new therapies will be dependent on full industry, academic and clinical collaborations to an extent that has not yet been realised.
www.current-opinion.com