The lipopeptide antibiotic daptomycin is a key drug used to treat some of the most worrisome bacterial pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus species (VRE).
Resistance among clinical isolates is currently still rare, but its frequency is increasing, and this problem will ultimately have to be addressed. With many classes of antibiotics, synthetic variation and optimization have been used to combat resistance and extend the drugs' useful lifespans.
In principle this should be possible with daptomycin as well but it has a complex structure, and previously described synthetic methods are laborious and not conducive to large scale synthetic variation.
Taylor and his postdoctoral fellow Chuda Lohani developed the first daptomycin synthesis that proceeds entirely on a solid phase. This makes it possible to synthesize hundreds of different daptomycin derivatives in parallel.
Each of these can then be tested individually against daptomycin-resistant bacterial strains. Compounds with improved activity can then be made on a larger scale and fully characterized through in vitro and in vivo studies.
The new method published in the journal Organic Letters, will also provide better tools for studying how daptomycin kills bacterial cells, as well as how bacteria become resistant to it.
Pictured above (left to right): Graduate student Robert Taylor, post-doctoral fellow Chuda Lohani and professors Scott Taylor and Michael Palmer.