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Cyclic peptides yield promising antimicrobial results
Newsdesk Cyclic peptides yield promising antimicrobial results Ghadiri’s hope that these new agents will be active against blood-borne infections, but first we need to find ways to reduce their haemolytic activity.” Shai also notes that the peptides’ biological stability—no enzymes in the body can digest them—needs to be reduced to prevent undesirable accumulation in the liver. Ghadiri responds that the resistance of the peptides to proteases is beneficial because it improves their bioavailability, but that they are nevertheless cleared safely from the body by other pathways. “These cyclic peptides certainly show some promise and a new
antibiotic class is badly needed”, comments Richard Wise (Birmingham University, UK), chair of the UK government’s advisory committee on antibiotic resistance. “There has only been one new class of antibiotics in the past 30 years”, he continues, “and already we are seeing resistance to it (Lancet 2001; 358: 207–08). These cyclic peptides act very rapidly, so maybe resistance to them will not develop. However, we must be cautious because, as sure as night follows day, resistance has followed use for every other antimicrobial we have developed”. Jane Bradbury
New rabies vaccine for India The development of an indigenous cell culture vaccine for rabies at the Pasteur Institute of India at Coonoor, south India, promises to deliver a safe vaccine for the local population, according to an article in the Times of India (July 12). Of the approximately 60 000 people who die of rabies annually worldwide, 3000 are from India alone.
Rights were not granted to include this image in electronic media. Please refer to the printed journal. Panos
Researchers at The Scripps Research Institute (La Jolla, CA, USA) reported in Nature recently that cyclic D,L-␣peptides can rapidly kill bacteria by forming “hole-punching” tubular nano-structures. “These peptides selfassemble into hollow tubes in response to their environment”, and because they each carry at least one basic aminoacid, they have an enhanced specificity towards negatively charged bacterial membranes compared with mammalian membranes”, explains lead author Reza Ghadiri. Animal experiments indicate that the peptides have in vivo activity against meticillin-resistant Staphylococcus aureus (MRSA) when injected intraperitoneally but, warns Ghadiri, “we are a long way from optimising these compounds for clinical use”. Cationic antimicrobial peptides—eg, defensins and protegrins— form part of the innate immune system in all species. Because of increasing bacterial resistance to existing antibiotics, antimicrobial peptides have attracted much attention over the past decade. The potential of cyclic peptides in vaccine development is also being recognised (see p 72). Although some antimicrobial peptides based on natural products are in phase III trials for topical use, none have proved useful systemically. Ghadiri’s team has now designed and tested a series of cyclic D,L-␣-peptides for activity against MRSA, Escherichia coli, and murine erthrocytes in vitro. Those peptides that showed greatest specificity for bacteria were then tested for toxicity and bacterial killing in mice (Nature 2001; 412: 452–55). “We saw limited toxicity and one dose of an active peptide was sufficient to kill intraperitoneally injected MRSA”, says Ghadiri. “Without the peptide, the mice died within 24–48 hours”. The researchers now plan to fine-tune peptide specificity and to do further animal studies. “These results are interesting and important”, says Yechiel Shai (Weizmann Institute of Science, Rehovot, Israel), who works on another class of potential antimicrobial peptides. “I share
Stray dogs in India roam the streets
The vaccine will be similar to the one called “Abhayrab” which was developed last year in Ootacamund (also in south India) by the Human Biological Institute, a unit of the National Dairy Development Board. It is produced with the vero-cell line as a substrate. These are cell lines derived from kidney cells of the vervet (African green) monkey. “Vero vaccines are considered to be safe by the WHO, with the recommendation that the DNA content of the vaccine be less than 300 pg/dose,” says S N Madhusudan, Associate Professor of
THE LANCET Infectious Diseases Vol 1 September 2001
Neurovirology at the National Institute of Mental Health and Neurosciences, Bangalore, where he leads a laboratory doing rabies vaccine research. Although there are no data on the actual potency of the vaccine, Madhusudan is optimisitic that it will be more than 2.5 IU/mL (the required potency). “About half the rabies vaccines used in India currently are the Semple sheep-brain rabies vaccine” he adds. The size of the country and the fact that there exists a significant rural population, which is exposed to dogs, means that many have access to only government-run hospitals and primary health centres where the Semple vaccine is used. These vaccines are cheap, but are painful (ten subcutaneous injections of 5 ml each), and carry the rare but serious potential risk of demyelination. The imported vero cell line vaccines are commonly used in the cities but are more expensive at around US$33 for the whole course. The new tissue culture vaccine on the other hand, should be available for about $15 since the Pasteur is a government institute that operates on a not-forprofit basis. However, the century-old institution will not be able to manufacture vaccines for the whole country. At best, it will be able to supply its own state of Tamil Nadu. Sanjay Pai
71
For personal use. Only reproduce with permission from The Lancet Publishing Group.
antibiotic class is badly needed”, comments Richard Wise (Birmingham University, UK), chair of the UK government’s advisory committee on antibiotic resistance. “There has only been one new class of antibiotics in the past 30 years”, he continues, “and already we are seeing resistance to it (Lancet 2001; 358: 207–08). These cyclic peptides act very rapidly, so maybe resistance to them will not develop. However, we must be cautious because, as sure as night follows day, resistance has followed use for every other antimicrobial we have developed”. Jane Bradbury
New rabies vaccine for India The development of an indigenous cell culture vaccine for rabies at the Pasteur Institute of India at Coonoor, south India, promises to deliver a safe vaccine for the local population, according to an article in the Times of India (July 12). Of the approximately 60 000 people who die of rabies annually worldwide, 3000 are from India alone.
Rights were not granted to include this image in electronic media. Please refer to the printed journal. Panos
Researchers at The Scripps Research Institute (La Jolla, CA, USA) reported in Nature recently that cyclic D,L-␣peptides can rapidly kill bacteria by forming “hole-punching” tubular nano-structures. “These peptides selfassemble into hollow tubes in response to their environment”, and because they each carry at least one basic aminoacid, they have an enhanced specificity towards negatively charged bacterial membranes compared with mammalian membranes”, explains lead author Reza Ghadiri. Animal experiments indicate that the peptides have in vivo activity against meticillin-resistant Staphylococcus aureus (MRSA) when injected intraperitoneally but, warns Ghadiri, “we are a long way from optimising these compounds for clinical use”. Cationic antimicrobial peptides—eg, defensins and protegrins— form part of the innate immune system in all species. Because of increasing bacterial resistance to existing antibiotics, antimicrobial peptides have attracted much attention over the past decade. The potential of cyclic peptides in vaccine development is also being recognised (see p 72). Although some antimicrobial peptides based on natural products are in phase III trials for topical use, none have proved useful systemically. Ghadiri’s team has now designed and tested a series of cyclic D,L-␣-peptides for activity against MRSA, Escherichia coli, and murine erthrocytes in vitro. Those peptides that showed greatest specificity for bacteria were then tested for toxicity and bacterial killing in mice (Nature 2001; 412: 452–55). “We saw limited toxicity and one dose of an active peptide was sufficient to kill intraperitoneally injected MRSA”, says Ghadiri. “Without the peptide, the mice died within 24–48 hours”. The researchers now plan to fine-tune peptide specificity and to do further animal studies. “These results are interesting and important”, says Yechiel Shai (Weizmann Institute of Science, Rehovot, Israel), who works on another class of potential antimicrobial peptides. “I share
Stray dogs in India roam the streets
The vaccine will be similar to the one called “Abhayrab” which was developed last year in Ootacamund (also in south India) by the Human Biological Institute, a unit of the National Dairy Development Board. It is produced with the vero-cell line as a substrate. These are cell lines derived from kidney cells of the vervet (African green) monkey. “Vero vaccines are considered to be safe by the WHO, with the recommendation that the DNA content of the vaccine be less than 300 pg/dose,” says S N Madhusudan, Associate Professor of
THE LANCET Infectious Diseases Vol 1 September 2001
Neurovirology at the National Institute of Mental Health and Neurosciences, Bangalore, where he leads a laboratory doing rabies vaccine research. Although there are no data on the actual potency of the vaccine, Madhusudan is optimisitic that it will be more than 2.5 IU/mL (the required potency). “About half the rabies vaccines used in India currently are the Semple sheep-brain rabies vaccine” he adds. The size of the country and the fact that there exists a significant rural population, which is exposed to dogs, means that many have access to only government-run hospitals and primary health centres where the Semple vaccine is used. These vaccines are cheap, but are painful (ten subcutaneous injections of 5 ml each), and carry the rare but serious potential risk of demyelination. The imported vero cell line vaccines are commonly used in the cities but are more expensive at around US$33 for the whole course. The new tissue culture vaccine on the other hand, should be available for about $15 since the Pasteur is a government institute that operates on a not-forprofit basis. However, the century-old institution will not be able to manufacture vaccines for the whole country. At best, it will be able to supply its own state of Tamil Nadu. Sanjay Pai
71
For personal use. Only reproduce with permission from The Lancet Publishing Group.