Fishovitz Jennifer, Rojas-Altuve Alzoray, Otero Lisandro H, Dawley Matthew, Carrasco-López Cesar, Chang Mayland, Hermoso Juan A, Mobashery Shahriar
Department of Chemistry and Biochemistry, University of Notre Dame , Nieuwland Science Hall, Notre Dame, Indiana 46556, United States.
J Am Chem Soc. 2014 Jul 16;136(28):9814-7. doi: 10.1021/ja5030657. Epub 2014 Jul 2.
Ceftaroline, a recently approved β-lactam antibiotic for treatment of infections by methicillin-resistant Staphylococcus aureus (MRSA), is able to inhibit penicillin-binding protein 2a (PBP2a) by triggering an allosteric conformational change that leads to the opening of the active site. The opened active site is now vulnerable to inhibition by a second molecule of ceftaroline, an event that impairs cell-wall biosynthesis and leads to bacterial death. The triggering of the allosteric effect takes place by binding of the first antibiotic molecule 60 Å away from the active site of PBP2a within the core of the allosteric site. We document, by kinetic studies and by determination of three X-ray structures of the mutant variants of PBP2a that result in resistance to ceftaroline, that the effect of these clinical mutants is the disruption of the allosteric trigger in this important protein in MRSA. This is an unprecedented mechanism for antibiotic resistance.
头孢洛林是一种最近被批准用于治疗耐甲氧西林金黄色葡萄球菌（MRSA）感染的β-内酰胺类抗生素，它能够通过引发变构构象变化来抑制青霉素结合蛋白2a（PBP2a），这种变化会导致活性位点打开。打开的活性位点现在容易受到第二个头孢洛林分子的抑制，这一事件会损害细胞壁生物合成并导致细菌死亡。变构效应的触发是通过第一个抗生素分子在变构位点核心内与PBP2a活性位点相距60 Å处结合而发生的。我们通过动力学研究以及对导致对头孢洛林耐药的PBP2a突变变体的三个X射线结构的测定证明，这些临床突变体的作用是破坏了MRSA中这种重要蛋白质的变构触发机制。这是一种前所未有的抗生素耐药机制。
