The structural basis for substrate versatility of chloramphenicol acetyltransferase CATI

Abstract

Novel antibiotics are needed to overcome the challenge of continually evolving bacterial resistance. This has led to a renewed interest in mechanistic studies of once popular antibiotics like chloramphenicol (CAM). Chloramphenicol acetyltransferases (CATs) are enzymes that covalently modify CAM, rendering it inactive against its target, the ribosome, and thereby causing resistance to CAM. Of the three major types of CAT (CATI-III), the CAM-specific CATIII has been studied extensively. Much less is known about another clinically important type, CATI. In addition to inactivating CAM and unlike CATIII, CATI confers resistance to a structurally distinct antibiotic, fusidic acid. The origin of the broader substrate specificity of CATI has not been fully elucidated. To understand the substrate binding features of CATI, its crystal structures in the unbound (apo) and CAM-bound forms were determined. The analysis of these and previously determined CATI-FA and CATIII-CAM structures revealed interactions responsible for CATI binding to its substrates and clarified the broader substrate preference of CATI compared to that of CATIII. Published by Wiley-Blackwell. © 2012 The Protein Society.