Target protection as a key antibiotic resistance mechanism

Antibiotic resistance is mediated through several distinct mechanisms, most of which are relatively well understood and the clinical importance of which has long been recognized. Until very recently, neither of these statements was readily applicable to the class of resistance mechanism known as target protection, a phenomenon whereby a resistance protein physically associates with an antibiotic target to rescue it from antibiotic-mediated inhibition. In this Review, we summarize recent progress in understanding the nature and importance of target protection. In particular, we describe the molecular basis of the known target protection systems, emphasizing that target protection does not involve a single, uniform mechanism but is instead brought about in several mechanistically distinct ways. During target protection, a resistance protein physically associates with an antibiotic target to rescue the latter from antibiotic-mediated inhibition. In this Review, O’Neill and colleagues describe the different molecular mechanisms underlying target protection and emphasize the importance of this phenomenon as a cause of clinically significant antibiotic resistance.