Fresh Molecular Concepts to Extend the Lifetimes of Old Antimicrobial Drugs.

Antimicrobial drug development generally initiates with target identification and mode of action studies. Often, emergence of resistance and/or undesired side effects that are discovered only after prolonged clinical use, result in discontinuation of clinical use. Since the cost and time required for improvement of existing drugs are considerably lower than those required for the development of novel drugs, academic and pharmaceutical company researchers pursue this direction. In this account we describe selected examples of how chemical probes generated from antimicrobial drugs and chemical and enzymatic modifications of these drugs have been used to modify modes of action, block mechanisms of resistance, or reduce side effects, improving performance. These examples demonstrate how new and comprehensive mechanistic insights can be translated into fresh concepts for development of next-generation antimicrobial agents.