Abstract

Glycopeptide antibiotics (GPAs) are the ‘last-resort’ drugs reserved for the treatment of serious drug-resistant Gram-positive infections. Their beneficial efficacies are exhaustively challenged by the emergence and distribution of GPA-resistant pathogens, vancomycin resistant enterococcus (VRE), in healthcare settings, propelling the innovative discovery/development of more effective GPAs. Type V GPAs provide a unique mode of action that enables them to be very promising lead compounds for drug discovery and development to combat drug-resistant and particularly VRE infections.

A team of researchers from McMaster has identified a new Type V GPA, rimomycin, that is active against VRE and Mycobacteria strains. After running medicinal chemistry campaigns on rimomycin, a lead compound has been identified that shows 8- and 16- fold decrease in minimum inhibition concentration (MIC) against VRE and Mycobacteria strains.  The McMaster team has developed a synthetic biology platform to enable the synthesis of these compounds at gram scale.

Applications

• The in vivo efficacy of the lead compound in the mouse systemic infection model demonstrates that it is a promising candidate to cure VRE A infections.

Advantages

• The lead compound contributes to a significant survival benefit against VRE A infection and prevents the invasive VRE A dissemination to blood and spleen.
• The lead compound exhibited no cytotoxicity or hemolytic activity.
• Compounds have a unique mechanism of action and negligible development of resistance.