Advancing 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 US Food and Drug Administration. One of the recently approved second-generation glycopeptides is dalbavancin, a semi-synthetic derivative of the natural product A40,926. This compound inhibits bacterial growth by binding to lipid intermediate II (Lipid II), a key intermediate in peptidoglycan biosynthesis. Like other recently approved antibiotics, dalbavancin has a complex history of preclinical and clinical development, with several companies contributing to different steps in different years. While our work on dalbavancin development stopped at the previous company, intriguingly our current pipeline includes two more Lipid II-binding natural products or derivatives thereof. In particular, we will focus on the properties of NAI-107 and related lantibiotics, which originated from recent screening and characterization efforts.
KeywordsGlycopeptide Teicoplanin Cell Wall Biosynthesis Semisynthetic Derivative Peptidoglycan Biosynthesis
This work was partially supported by the European Community’s Seventh Framework Programme (FP7/2007–2013) under grant agreements 289285 (TRAIN-ASAP) and 245066 (LAPTOP) and by a joint grant from Regione Lombardia and Italian Ministry of Education, University and Research (ProjectID 30190679).
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