Bacterial Pathogenesis Group, Institut de Biologie Structurale, Université Grenoble I, France.
ACS Chem Biol. 2011 Sep 16;6(9):943-51. doi: 10.1021/cb2001846. Epub 2011 Aug 3.
β-Lactam antibiotics have long been a treatment of choice for bacterial infections since they bind irreversibly to Penicillin-Binding Proteins (PBPs), enzymes that are vital for cell wall biosynthesis. Many pathogens express drug-insensitive PBPs rendering β-lactams ineffective, revealing a need for new types of PBP inhibitors active against resistant strains. We have identified alkyl boronic acids that are active against pathogens including methicillin-resistant S. aureus (MRSA). The crystal structures of PBP1b complexed to 11 different alkyl boronates demonstrate that in vivo efficacy correlates with the mode of inhibitor side chain binding. Staphylococcal membrane analyses reveal that the most potent alkyl boronate targets PBP1, an autolysis system regulator, and PBP2a, a low β-lactam affinity enzyme. This work demonstrates the potential of boronate-based PBP inhibitors for circumventing β-lactam resistance and opens avenues for the development of novel antibiotics that target Gram-positive pathogens.
β-内酰胺类抗生素通过不可逆地与青霉素结合蛋白（PBPs）结合，成为治疗细菌感染的首选药物，后者是细胞壁生物合成所必需的酶。许多病原体表达对药物不敏感的 PBPs，使β-内酰胺类抗生素无效，这凸显了开发针对耐药菌株的新型 PBPs 抑制剂的必要性。我们已经发现了烷基硼酸酯，它们对包括耐甲氧西林金黄色葡萄球菌（MRSA）在内的病原体具有活性。与 11 种不同烷基硼酸酯结合的 PBP1b 的晶体结构表明，体内疗效与抑制剂侧链结合模式相关。葡萄球菌膜分析表明，最有效的烷基硼酸酯靶向 PBP1，这是一种自溶系统调节剂，以及 PBP2a，这是一种对β-内酰胺亲和力低的酶。这项工作证明了基于硼酸酯的 PBPs 抑制剂克服β-内酰胺类抗生素耐药性的潜力，并为开发针对革兰氏阳性病原体的新型抗生素开辟了途径。
