Advancing new cell wall inhibitors towards clinical applications

Natural products represent a major source of approved drugs and still play an important role in supplying chemical diversity. Consistently, 2014 has seen new, natural product-derived antibiotics approved for human use by the FDA. One of the recently approved second-generation glycopeptides is dalbavancin, a semi-synthetic derivative of the glycopeptide A40,926, produced by the actinomycete Nonomuraea sp.. This compound inhibits bacterial growth by binding to lipid II, a key intermediate in peptidoglycan biosynthesis. Like other recently approved antibiotics, dalbavancin has a complex history and key events leading to its approval will be reported. Also originating from the Naicons' collection of actinomycete strains, a series of lantibiotics have been discovered and characterized. These compounds also target lipid II, but bind to different site from glycopeptides and are thus equally effective on vancomycin-resistant strains. The most active compound, designated NAI-107 and produced by the actinomycete Microbispora sp., is highly active against most Gram-positive pathogens, independent of their resistance mechanisms. It is rapidly bactericidal at concentrations close to the MIC and efficacious in several experimental models of infection. It is currently in advanced preclinical characterization. Additional actinomycete-derived compounds in the series include natural and semi-synthetic variants with similar potency but different physico-chemical properties.