- Email: [email protected]
Antimicrobials
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Antimicrobials Editorial overview Patrice Courvalin* and Julian Davies† Addresses *Institut Pasteur, Unité des Agents Antibacteriens, 28 Rue du Dr Roux, F-75724, Paris Cedex 15, France; e-mail: [email protected] † Department of Microbiology, University of British Columbia, 300-6174 University Boulevard, Vancouver, BC V6T 1Z3, Canada; e-mail: [email protected] Current Opinion in Microbiology 1999, 2:465–466 1369-5274/99/$ — see front matter © 1999 Elsevier Science Ltd. All rights reserved.
Since the 1950s, antibiotics have been the cornerstone of antibacterial therapy world-wide; these agents are active against identified diseases in humans, animals and plants. Antibiotics may be static or bactericidal in action, although the reasons for different activities have not been completely defined. For example, why is chloramphenicol a bacteristatic drug for most bacterial species but has killing activity against Haemophilus influenzae? Many questions remain about antibiotics but their use is unabated. The most significant outcome of the use of antibiotics, apart from the increase in human life expectancy, has been the ubiquitous development of antibiotic resistance. The appearance of pathogenic bacteria and fungi resistant to one (mostly more) antibiotic agent is now the most serious threat to antibiotic use and must be solved as we move into the next century. There are a number of potential solutions to this problem of which the principal ones are, firstly, the discovery of novel antimicrobial agents that have unique targets such that cross-resistance does not readily occur and, secondly, a better understanding of how antibiotic resistance develops and how it is maintained. The reviews presented here outline current studies that address these issues. Erythromycin (a macrolide) and its various derivatives have been used for the treatment of Gram-positive infections for almost 40 years: this antibiotic has appeared in related forms (clarithromycin, azithromycin) that have seen extensive use more recently and are indicated for a number of important infections. However, the development of resistance to erythromycin derivatives is a problem and structures that avoid this drawback are being sought. Amongst these is the new generation of ketolides. In the first article in this issue, Chu reviews the current activity in this field (pp 467–474). The Interscience Congress on Antimicrobial Agents and Chemotherapy (ICAAC) has been held yearly almost since the beginning of the antibiotic era. It is attended by representatives of almost every pharmaceutical company, as well as many physicians and clinical microbiologists; it is at this meeting that “what is new in antibiotics” is revealed. We have taken this opportunity to have Lee, Miller and Yagisawa present their own conclusions of the 1998 ICAAC
meeting (pp 475–482). It is hoped that such a summary can be made available on an annual basis. There are many aspects of antibiotic resistance that are worthy of discussion and three reviews covering different, but equally important, aspects of the subject follow. The principal mechanisms of antibiotic resistance in bacterial pathogens are encoded by acquired genes (from where, we do not know!), and the review by Rowe-Magnus and Mazel (pp 483–488) summarises the current status of the genetic mechanisms responsible for heterologous gene acquisition and expression. These genetic mechanisms are likely to have played roles in the evolution of species. Once a microbe has become resistant to an antibiotic, it cannot be assumed that everything is fine and dandy for the protected bug because acquisition of resistance (by mutation or inheritance) comes at a cost and it is known that a resistant strain does not compete well with its susceptible progenitor under normal growth conditions. Andersson and Levin (pp 489–493) describe this situation and review various studies that show how the crafty bacteria develop additional mutations to compensate for the lack of fitness. The most valuable studies of antibiotic use and resistance come from applications in human populations. Guillemot (pp 494–498) summaries several studies of the development of antibiotic resistance as a public health problem and indicates the ways in which the problem may be alleviated if not resolved completely. From the point of view of a pharmaceutical company, the challenge is finding other antibiotics that will have potent activity against strains resistant to the available antibiotics. One approach to this end is the development of a comprehensive understanding of resistance mechanisms and to use this information to design inhibitors of the resistance mechanisms that revivify the defunct antibiotics. This approach has been used successfully with β-lactam antibiotics, and Wright (pp 499–503) presents a detailed review of the mechanisms of resistance to aminoglycoside antibiotics including suggestions as to how this knowledge can be used to expand the use of aminoglycosides. For rational antibiotic design, a profound knowledge of the way in which different antibiotics act on their various targets is an essential first step. The fluoroquinolones as a class are one of the most extensively used antibiotics world-wide and the way in which they block replication of sensitive bacteria has been difficult to solve. Drlica (pp 504–508) provides a detailed analysis of the complexity of the interaction between fluoroquinolones and the prokaryotic replication system.
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Antimicrobials
The final review by DiDomenico (pp 509–515) presents an assessment of developments in the search for novel antifungal agents. With serious antifungal infections on the increase and the problem of antibiotic resistance eroding the use of current agents, there is a pressing need for effective and non-toxic antifungal agents.
It is apparent that infectious diseases will remain the major cause of morbidity and mortality in humans and animals for the foreseeable future. The threats of existing pathogens, now augmented by emerging and re-emerging pathogens, require constant vigilance and good defences; in other words, high quality surveillance and new antimicrobial agents are a must!
11/09/1999 2:51 PM
Page 465
465
Antimicrobials Editorial overview Patrice Courvalin* and Julian Davies† Addresses *Institut Pasteur, Unité des Agents Antibacteriens, 28 Rue du Dr Roux, F-75724, Paris Cedex 15, France; e-mail: [email protected] † Department of Microbiology, University of British Columbia, 300-6174 University Boulevard, Vancouver, BC V6T 1Z3, Canada; e-mail: [email protected] Current Opinion in Microbiology 1999, 2:465–466 1369-5274/99/$ — see front matter © 1999 Elsevier Science Ltd. All rights reserved.
Since the 1950s, antibiotics have been the cornerstone of antibacterial therapy world-wide; these agents are active against identified diseases in humans, animals and plants. Antibiotics may be static or bactericidal in action, although the reasons for different activities have not been completely defined. For example, why is chloramphenicol a bacteristatic drug for most bacterial species but has killing activity against Haemophilus influenzae? Many questions remain about antibiotics but their use is unabated. The most significant outcome of the use of antibiotics, apart from the increase in human life expectancy, has been the ubiquitous development of antibiotic resistance. The appearance of pathogenic bacteria and fungi resistant to one (mostly more) antibiotic agent is now the most serious threat to antibiotic use and must be solved as we move into the next century. There are a number of potential solutions to this problem of which the principal ones are, firstly, the discovery of novel antimicrobial agents that have unique targets such that cross-resistance does not readily occur and, secondly, a better understanding of how antibiotic resistance develops and how it is maintained. The reviews presented here outline current studies that address these issues. Erythromycin (a macrolide) and its various derivatives have been used for the treatment of Gram-positive infections for almost 40 years: this antibiotic has appeared in related forms (clarithromycin, azithromycin) that have seen extensive use more recently and are indicated for a number of important infections. However, the development of resistance to erythromycin derivatives is a problem and structures that avoid this drawback are being sought. Amongst these is the new generation of ketolides. In the first article in this issue, Chu reviews the current activity in this field (pp 467–474). The Interscience Congress on Antimicrobial Agents and Chemotherapy (ICAAC) has been held yearly almost since the beginning of the antibiotic era. It is attended by representatives of almost every pharmaceutical company, as well as many physicians and clinical microbiologists; it is at this meeting that “what is new in antibiotics” is revealed. We have taken this opportunity to have Lee, Miller and Yagisawa present their own conclusions of the 1998 ICAAC
meeting (pp 475–482). It is hoped that such a summary can be made available on an annual basis. There are many aspects of antibiotic resistance that are worthy of discussion and three reviews covering different, but equally important, aspects of the subject follow. The principal mechanisms of antibiotic resistance in bacterial pathogens are encoded by acquired genes (from where, we do not know!), and the review by Rowe-Magnus and Mazel (pp 483–488) summarises the current status of the genetic mechanisms responsible for heterologous gene acquisition and expression. These genetic mechanisms are likely to have played roles in the evolution of species. Once a microbe has become resistant to an antibiotic, it cannot be assumed that everything is fine and dandy for the protected bug because acquisition of resistance (by mutation or inheritance) comes at a cost and it is known that a resistant strain does not compete well with its susceptible progenitor under normal growth conditions. Andersson and Levin (pp 489–493) describe this situation and review various studies that show how the crafty bacteria develop additional mutations to compensate for the lack of fitness. The most valuable studies of antibiotic use and resistance come from applications in human populations. Guillemot (pp 494–498) summaries several studies of the development of antibiotic resistance as a public health problem and indicates the ways in which the problem may be alleviated if not resolved completely. From the point of view of a pharmaceutical company, the challenge is finding other antibiotics that will have potent activity against strains resistant to the available antibiotics. One approach to this end is the development of a comprehensive understanding of resistance mechanisms and to use this information to design inhibitors of the resistance mechanisms that revivify the defunct antibiotics. This approach has been used successfully with β-lactam antibiotics, and Wright (pp 499–503) presents a detailed review of the mechanisms of resistance to aminoglycoside antibiotics including suggestions as to how this knowledge can be used to expand the use of aminoglycosides. For rational antibiotic design, a profound knowledge of the way in which different antibiotics act on their various targets is an essential first step. The fluoroquinolones as a class are one of the most extensively used antibiotics world-wide and the way in which they block replication of sensitive bacteria has been difficult to solve. Drlica (pp 504–508) provides a detailed analysis of the complexity of the interaction between fluoroquinolones and the prokaryotic replication system.
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Page 466
Antimicrobials
The final review by DiDomenico (pp 509–515) presents an assessment of developments in the search for novel antifungal agents. With serious antifungal infections on the increase and the problem of antibiotic resistance eroding the use of current agents, there is a pressing need for effective and non-toxic antifungal agents.
It is apparent that infectious diseases will remain the major cause of morbidity and mortality in humans and animals for the foreseeable future. The threats of existing pathogens, now augmented by emerging and re-emerging pathogens, require constant vigilance and good defences; in other words, high quality surveillance and new antimicrobial agents are a must!