The emergence and dissemination of multidrug resistant (MDR) pathogens resistant to nearly all available antibiotics poses a significant threat in clinical therapy. Among them, Klebsiella pneumoniae clinical isolates overexpressing KPC‐2 carbapenemase are the most worrisome, extending bacterial resistance to last‐resort carbapenems. In this study, we investigate the molecular recognition requirements in the KPC‐2 active site by small phenylboronic acid derivatives. Four new phenylboronic acid derivatives were designed and tested against KPC‐2. For the most active, despite their simple chemical structures, nanomolar affinity was achieved. The new derivatives restored susceptibility to meropenem in clinical strains overexpressing KPC‐2. Moreover, no cytotoxicity was detected in cell‐viability assays, which further validated the designed leads. Two crystallographic binary complexes of the best inhibitors binding KPC‐2 were obtained at high resolution. Kinetic descriptions of slow binding, time‐dependent inhibition, and interaction geometries in KPC‐2 were fully investigated. This study will ultimately lead toward the optimization and development of more‐effective KPC‐2 inhibitors.

中文翻译：

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苯硼酸衍生物作为有效的线索在过表达KPC-2的临床菌株中起作用：对抗细菌耐药性的步骤

对几乎所有可用抗生素具有耐药性的多药耐药（MDR）病原体的出现和传播在临床治疗中构成了重大威胁。其中，肺炎克雷伯菌过度表达KPC-2碳青霉烯酶的临床分离株是最令人担忧的，将细菌耐药性扩展到最后一种碳青霉烯类。在这项研究中，我们研究了小苯基硼酸衍生物在KPC-2活性位点的分子识别要求。针对KPC-2设计并测试了四种新的苯基硼酸衍生物。对于最活跃的分子，尽管其化学结构简单，但仍可实现纳摩尔亲和力。新的衍生物恢复了过表达KPC-2的临床菌株对美洛培南的敏感性。此外，在细胞活力测定中未检测到细胞毒性，这进一步验证了设计的潜在顾客。在高分辨率下获得了两种最佳抑制剂结合KPC-2的晶体学二元复合物。慢结合，时间依赖性抑制，并全面研究了KPC-2中的相互作用几何。这项研究最终将导致优化和开发更有效的KPC-2抑制剂。