Looking for new magic bullets: Identification and development of bacteriophage lysins
Raymond Schuch, The Rockefeller University

Despite the increasing prevalence of antibiotic resistance among pathogenic bacteria, research into anti-microbial agents has, astonishingly enough, declined since the 1980’s. The bioterrorist attack of fall 2001 in the United States has, however, spurred renewed interest in the area of novel therapeutics. Toward this end, we are developing a new antibiotic therapy that exploits an enzyme family, termed lysins, normally used by bacterial viruses to degrade the bacterial cell wall during infection and effect progeny virus release. Our work is largely based on findings that small quantities of purified recombinant lysins can be added extrinsically to disease-causing bacteria to elicit a rapid killing effect. Evaluation of the therapeutic potential for lysin began with a series of genetic- and genomic-based approaches to identify lysins active against the biological weapon, and inhalational anthrax agent, Bacillus anthracis. A B. anthracis-specific lysin, PlyG, was purified and found to exert a powerful bacteriocidal effect in a variety of laboratory conditions, including the bloodstream of animals infected with anthrax. Interestingly, in the course of our work we failed to detect lysin-resistant bacteria, even in conditions favoring resistance to conventional antibiotics. The therapeutic effect, combined with the lack of resistance, make lysins attractive target for development not only for treatment of anthrax, but a variety of other infections as well, including life-threatening and multidrug-resistant pathogens like pneumococci, staphylococci, and enterococci. Thus, lysins may provide a much needed anti-infective in an age of mounting drug-resistance.

Additional Reading:

Projan, S.J. 2003. Why is big Pharma getting out of antibacterial drug discovery? Curr. Opin. Microbiolol. 6:427-30.

Schuch R, Nelson, D., Fischetti, V.A. 2002. A bacteriolytic agent that detects and kills Bacillus anthracis. Nature. 418:884-889.

Loeffler J.M., Nelson D., Fischetti V.A. 2001. Rapid killing of Streptococcus pneumoniae with a bacteriophage cell wall hydrolase. Science. 294:2170-2

Mock M., Fouet A. 2001. Anthrax. Annu Rev Microbiol. 55:647-71.

Weinbauer M.G., 2004. Ecology of prokaryotic viruses. FEMS Microbiol Rev. 28:127-81.

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