关于硼酸β-内酰胺酶抑制剂的结构演变与临床证据的综述。
完整摘要 · 中文译文
耐碳青霉烯类革兰阴性杆菌的播散使β-内酰胺/β-内酰胺酶抑制剂（BLI）联合方案成为治疗的核心。硼酸是唯一一类在化学上原则上可覆盖全部四类Ambler酶的BLI，硼与催化丝氨酸形成四面体加合物，同时还能配位金属-β-内酰胺酶的锌离子。检索了截至2026年9月30日的PubMed/MEDLINE和Web of Science，以及ClinicalTrials.gov和蛋白质数据银行，获取关于法硼巴坦、他尼硼巴坦和泽鲁硼巴坦的结构、生化、监测和临床数据。三代化合物在酶类层面进行了比较，二氮杂双环辛烷类药物度洛巴坦作为机制对照，关键性3期试验则按酶指导治疗的要求进行评估。该支架已从选择性抑制KPC的单环化合物发展为在纳摩尔浓度下体外抑制丝氨酸酶和B1亚类金属-β-内酰胺酶的双环化合物，但这一广度在临床上尚未充分实现。各实验室之间报告的效力相差一到两个数量级，对IMP、SPM和B3亚类酶的覆盖尚不完整，且没有任何一项注册试验围绕碳青霉烯酶基因型设计。伙伴β-内酰胺的选择和试验设计目前对领域的制约已超过靶点结合本身。
完整摘要 · 英文原文
The spread of carbapenem-resistant Gram-negative bacilli has made β-lactam/β-lactamase inhibitor (BLI) combinations central to therapy. Boronic acids are the only BLI class whose chemistry can in principle reach all four Ambler classes, boron forms a tetrahedral adduct with the catalytic serine and can also coordinate the zinc ions of metallo-β-lactamases. PubMed/MEDLINE and Web of Science were searched to 30 September 2026, together with ClinicalTrials.gov and the Protein Data Bank, for structural, biochemical, surveillance, and clinical data on vaborbactam, taniborbactam, and xeruborbactam. The three generations are compared across enzyme classes, the diazabicyclooctane durlobactam is used as a mechanistic comparator, and the pivotal phase 3 trials are appraised against the requirements of enzyme-guided therapy. The scaffold has advanced from KPC-selective monocyclic to bicyclic compounds that inhibit serine and subclass B1 metallo-β-lactamases in vitro at nanomolar concentrations, but this breadth remains largely unrealized clinically. Reported potencies differ by one to two orders of magnitude between laboratories, coverage of IMP, SPM, and subclass B3 enzymes is incomplete, and no registrational trial has been designed around carbapenemase genotype. Partner β-lactam selection and trial design now constrain the field more than target engagement does.