The Structural Bases of Antibiotic Resistance

Widespread use of -lactam antibiotics has promoted the evolution of -lactamase mutant enzymes that can hydrolyze ever newer classes of these drugs. Among the most pernicious mutants are the inhibitor-resistant TEM -lactamases (IRTs), which elude mechanism-based inhibitors, such as clavulanate. Despite much re-search on these IRTs, little is known about the struc-tural bases of their action. This has made it difficult to understand how many of the resistance substitutions act as they often occur far from Ser-130. Here, three IRT structures, TEM-30 (R244S), TEM-32 (M69I/M182T), and TEM-34 (M69V), are determined by x-ray crystallogra-phy at 2.00, 1.61, and 1.52 Å, respectively. In TEM-30, the Arg-2443 Ser substitution (7.8 Å from Ser-130) displaces a conserved water molecule that usually interacts wit