Đây là bài khá hay dành cho các bạn yêu thích vi sinh học phân tử. Bài PDF có đính kèm. Bài dịch sẽ được chỉnh sửa để làm bản tin index, bản quyền bản dịch sẽ thuộc về tác giả.
News and Views
Nature 438, 170-171 (10 November 2005) | doi:10.1038/438170a
Microbiology: RAMP resistance
Angus Buckling1 and Michael Brockhurst2
Top of page
Abstract
There is an urgent need for new antimicrobial agents because antibiotic resistance has become so prevalent. But a promising class of such agents, known as RAMPs, may suffer from the same problem.
In a report published in Proceedings of the Royal Society, Perron et al.1 demonstrate experi- mentally that bacteria can readily evolve resistance to a group of proteins called ribosomally encoded antimicrobial peptides (RAMPs). RAMPS are produced by animals, plants, fungi and bacteria as part of their natural defence against microbial attack2, 3, 4, and are being developed as antibiotics. But because bacterial resistance to chemotherapeutic RAMPs could confer resistance to the battery of innate human RAMPs4, the worrying prospect is that widespread use of these agents may compromise our natural defence against bacteria.
With the emergence of bacteria that are resistant to 'last resort' antibiotics such as vancomycin5, there is a desperate need to identify new antimicrobial agents. RAMPs may be just such agents. They are a diverse group of proteins, and their mode of action varies considerably, but a common feature is their positive charge. This allows them to bind to the negatively charged membranes of bacteria. The effectiveness of a variety of RAMPs in clinical trials2, 3, and the recent discovery of fungus-derived RAMPs that can be produced in large yields3, suggest RAMPs could be in widespread clinical use within the next few years.
The potential advantages of RAMPs are the apparent difficulty that bacteria face in evolving resistance to them, and the fact that resistance to conventional antibiotics does not seem to confer resistance to RAMPs2. Bacteria have obviously encountered RAMPs in one form or another for millions of years, yet widespread resistance is rare. Furthermore, previous experimental tests suggest that the evolution of resistance does not readily occur6, 7.
However, resistance evolution is all about the level of exposure. Although bacteria had been exposed to natural antibiotics such as penicillin and streptomycin (respectively produced by the Penicillium mould and Streptomyces bacteria) for millions of years, resistance was at low levels when widespread clinical use of these drugs began in the 1940s. But after a few years of exposure to high clinical doses, resistance was widespread in many species of pathogenic bacteria.
On the basis of such logic, Perron et al.1 attempted to experimentally induce resistance to a RAMP in two different bacterial species, Escherichia coli and Pseudomonas fluorescens. The RAMP in question, pexiganan, is a synthetic analogue of a RAMP derived from toads (magainin) that has been modified for use as a chemotherapeutic agent. The authors exposed bacteria to slowly increasing concentrations of the drug for 600 generations (a few months in the lab), unlike previous work where drug concentrations were kept constant, and populations were allowed to evolve for no more than 200 generations6, 7. The results were astounding: 22 out of 24 populations of bacteria had developed resistance to the drug.
The ability of bacteria to evolve resistance to antibiotics does not necessarily mean that resistance will become a widespread problem. Antibiotic resistance often compromises the bacteria in other ways — for example, by reducing their growth rate8. This means that antibiotic-sensitive bacteria will outcompete the resistant forms when neither is exposed to the antibiotic. Perron et al.1 investigated this possibility, and indeed found a 'cost' of antibiotic resistance: in the absence of the antibiotic, resistant bacteria took longer to start reproducing than control bacteria, although once they had got going, their replication rate was unaffected.
Unfortunately, bacteria have other tricks up their sleeves. In addition to adapting to antibiotics, they can also adapt to antibiotic resistance. There have been numerous cases of bacteria with antibiotic resistance developing mutations in other parts of their genome that compensate for the associated costs8, 9. These adaptations are sometimes so specific that the growth rate of bacteria can decrease if the genetic changes conferring antibiotic resistance are replaced with the original sensitive form of the gene after compensatory adaptation has occurred9.
Why should bacterial resistance to RAMPs cause more concern than resistance to other antibiotics? The major problem will be if resistance to chemotherapeutic RAMPs also confers resistance to naturally occurring RAMPs in humans and other organisms. Bacteria that are normally dealt with unnoticed by our innate immune system may then cause serious infections. Large-scale use of chemotherapeutic RAMPs may ultimately help pathogenic bacteria colonize parts of animals and plants that were previously off limits to them.
This perspective may be overstating the case for concern. Humans alone produce a highly diverse arsenal of RAMPs, which are also thought to be constantly evolving new ways of targeting bacteria1; and RAMPs constitute only one part of our natural immunity. Furthermore, RAMP resistance, where observed, is often specific to a small range of RAMPs4. There are exceptions, however. A variety of bacteria, including Staphylococcus aureus — famed for methicillin resistance — and the opportunistic pathogen Pseudomonas aeruginosa have evolved a degree of generalized RAMP resistance by increasing the amount of positively charged protein in their membranes. The consequence may be to reduce the binding efficiency of the positively charged RAMPs10.
As Perron et al.1, and others2, 3, 4, emphasize, RAMPs are likely to make a major contribution to human health and agriculture. But given the prospect of resistance, extra caution is necessary in developing and using them.
Top of page
References
Perron, G. G., Zasloff, M. & Bell, G. Proc. R. Soc. Lond. B doi:rspb.2005.3301 (2005).
Zasloff, M. Nature 415, 389–395 (2002). | Article |
Mygind, P. H. et al. Nature 437, 975–980 (2005). | Article |
Bell, G. & Gouyon, P. -H. Microbiology 149, 1367–1375 (2003). | Article |
Trevor, F. C. & McDonald, L. C. Curr. Opin. Infect. Dis. 18, 300–305 (2005).
Ge, Y. et al. Antimicrob. Agents Chemother. 43, 782–788 (1999).
Steinberg, D. A. et al. Antimicrob. Agents Chemother. 41, 1738–1742 (1997).
Maisnier-Patin, S. & Andersson, D. S. Res. Microbiol. 150, 360–369 (2004). | Article |
Schrag, S. J. et al. Proc. R. Soc. Lond. B 264, 1287–1291 (1997). | Article |
Fedtke, I., Gotz, F. & Peschel, A. Int. J. Med. Microbiol. 294, 189–194 (2004). | Article |
News and Views
Nature 438, 170-171 (10 November 2005) | doi:10.1038/438170a
Microbiology: RAMP resistance
Angus Buckling1 and Michael Brockhurst2
Top of page
Abstract
There is an urgent need for new antimicrobial agents because antibiotic resistance has become so prevalent. But a promising class of such agents, known as RAMPs, may suffer from the same problem.
In a report published in Proceedings of the Royal Society, Perron et al.1 demonstrate experi- mentally that bacteria can readily evolve resistance to a group of proteins called ribosomally encoded antimicrobial peptides (RAMPs). RAMPS are produced by animals, plants, fungi and bacteria as part of their natural defence against microbial attack2, 3, 4, and are being developed as antibiotics. But because bacterial resistance to chemotherapeutic RAMPs could confer resistance to the battery of innate human RAMPs4, the worrying prospect is that widespread use of these agents may compromise our natural defence against bacteria.
With the emergence of bacteria that are resistant to 'last resort' antibiotics such as vancomycin5, there is a desperate need to identify new antimicrobial agents. RAMPs may be just such agents. They are a diverse group of proteins, and their mode of action varies considerably, but a common feature is their positive charge. This allows them to bind to the negatively charged membranes of bacteria. The effectiveness of a variety of RAMPs in clinical trials2, 3, and the recent discovery of fungus-derived RAMPs that can be produced in large yields3, suggest RAMPs could be in widespread clinical use within the next few years.
The potential advantages of RAMPs are the apparent difficulty that bacteria face in evolving resistance to them, and the fact that resistance to conventional antibiotics does not seem to confer resistance to RAMPs2. Bacteria have obviously encountered RAMPs in one form or another for millions of years, yet widespread resistance is rare. Furthermore, previous experimental tests suggest that the evolution of resistance does not readily occur6, 7.
However, resistance evolution is all about the level of exposure. Although bacteria had been exposed to natural antibiotics such as penicillin and streptomycin (respectively produced by the Penicillium mould and Streptomyces bacteria) for millions of years, resistance was at low levels when widespread clinical use of these drugs began in the 1940s. But after a few years of exposure to high clinical doses, resistance was widespread in many species of pathogenic bacteria.
On the basis of such logic, Perron et al.1 attempted to experimentally induce resistance to a RAMP in two different bacterial species, Escherichia coli and Pseudomonas fluorescens. The RAMP in question, pexiganan, is a synthetic analogue of a RAMP derived from toads (magainin) that has been modified for use as a chemotherapeutic agent. The authors exposed bacteria to slowly increasing concentrations of the drug for 600 generations (a few months in the lab), unlike previous work where drug concentrations were kept constant, and populations were allowed to evolve for no more than 200 generations6, 7. The results were astounding: 22 out of 24 populations of bacteria had developed resistance to the drug.
The ability of bacteria to evolve resistance to antibiotics does not necessarily mean that resistance will become a widespread problem. Antibiotic resistance often compromises the bacteria in other ways — for example, by reducing their growth rate8. This means that antibiotic-sensitive bacteria will outcompete the resistant forms when neither is exposed to the antibiotic. Perron et al.1 investigated this possibility, and indeed found a 'cost' of antibiotic resistance: in the absence of the antibiotic, resistant bacteria took longer to start reproducing than control bacteria, although once they had got going, their replication rate was unaffected.
Unfortunately, bacteria have other tricks up their sleeves. In addition to adapting to antibiotics, they can also adapt to antibiotic resistance. There have been numerous cases of bacteria with antibiotic resistance developing mutations in other parts of their genome that compensate for the associated costs8, 9. These adaptations are sometimes so specific that the growth rate of bacteria can decrease if the genetic changes conferring antibiotic resistance are replaced with the original sensitive form of the gene after compensatory adaptation has occurred9.
Why should bacterial resistance to RAMPs cause more concern than resistance to other antibiotics? The major problem will be if resistance to chemotherapeutic RAMPs also confers resistance to naturally occurring RAMPs in humans and other organisms. Bacteria that are normally dealt with unnoticed by our innate immune system may then cause serious infections. Large-scale use of chemotherapeutic RAMPs may ultimately help pathogenic bacteria colonize parts of animals and plants that were previously off limits to them.
This perspective may be overstating the case for concern. Humans alone produce a highly diverse arsenal of RAMPs, which are also thought to be constantly evolving new ways of targeting bacteria1; and RAMPs constitute only one part of our natural immunity. Furthermore, RAMP resistance, where observed, is often specific to a small range of RAMPs4. There are exceptions, however. A variety of bacteria, including Staphylococcus aureus — famed for methicillin resistance — and the opportunistic pathogen Pseudomonas aeruginosa have evolved a degree of generalized RAMP resistance by increasing the amount of positively charged protein in their membranes. The consequence may be to reduce the binding efficiency of the positively charged RAMPs10.
As Perron et al.1, and others2, 3, 4, emphasize, RAMPs are likely to make a major contribution to human health and agriculture. But given the prospect of resistance, extra caution is necessary in developing and using them.
Top of page
References
Perron, G. G., Zasloff, M. & Bell, G. Proc. R. Soc. Lond. B doi:rspb.2005.3301 (2005).
Zasloff, M. Nature 415, 389–395 (2002). | Article |
Mygind, P. H. et al. Nature 437, 975–980 (2005). | Article |
Bell, G. & Gouyon, P. -H. Microbiology 149, 1367–1375 (2003). | Article |
Trevor, F. C. & McDonald, L. C. Curr. Opin. Infect. Dis. 18, 300–305 (2005).
Ge, Y. et al. Antimicrob. Agents Chemother. 43, 782–788 (1999).
Steinberg, D. A. et al. Antimicrob. Agents Chemother. 41, 1738–1742 (1997).
Maisnier-Patin, S. & Andersson, D. S. Res. Microbiol. 150, 360–369 (2004). | Article |
Schrag, S. J. et al. Proc. R. Soc. Lond. B 264, 1287–1291 (1997). | Article |
Fedtke, I., Gotz, F. & Peschel, A. Int. J. Med. Microbiol. 294, 189–194 (2004). | Article |