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 (CAT_I‐III), the CAM‐specific CAT_III has been studied extensively. Much less is known about another clinically important type, CAT_I. In addition to inactivating CAM and unlike CAT_III, CAT_I confers resistance to a structurally distinct antibiotic, fusidic acid. The origin of the broader substrate specificity of CAT_I has not been fully elucidated. To understand the substrate binding features of CAT_I, its crystal structures in the unbound (apo) and CAM‐bound forms were determined. The analysis of these and previously determined CAT_I‐FA and CAT_III‐CAM structures revealed interactions responsible for CAT_I binding to its substrates and clarified the broader substrate preference of CAT_I compared to that of CAT_III.