New Antiobiotic Targets Hospital Pathogens

Researchers from Merck Research Laboratories (Rahway, NJ, USA) have discovered an antibiotic named platensimycin that is a member of a formerly unknown class of antimicrobials produced by Streptomyces platensis. Platensimycin has potent, broad-spectrum activity against Gram-positive microbes, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococcus (VRE).

The drug works by selectively blocking cellular lipid biosynthesis. In particular, it targets FabF/B, an enzyme involved in fatty-acid synthesis. Direct binding assays show that platensimycin interacts specifically with the acyl-enzyme intermediate of the target protein, and x-ray crystallographic studies reveal that a specific conformational change that occurs on acylation must take place before the inhibitor can bind. In culture and animal studies, tests showed activity against a variety of drug-resistant organisms, including MRSA, VRE, and vancomycin-intermediate S aureus. The discovery was reported in a letter published in the May 18, 2006, issue of Nature.

"In bacteria, fatty-acid synthesis is generated by building up long carbon chains. These carbon chains are built up in two carbon units that are successively added on to the chain as it grows, and this antibiotic targets the enzyme which is the chain-building enzyme,” said co-author Dr. Stephen Soisson. "And by inhibiting that, very specifically, it shuts down fatty-acid synthesis which is absolutely essential for the bacteria to grow.”

"Platensimycin is the most potent inhibitor for the FabF/B condensing enzymes, and is the only inhibitor of these targets that shows broad-spectrum activity, in vivo efficacy, and no observed toxicity, noted lead author Dr. Jun Wang and colleagues.



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