Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, New Jersey 08854, United States.
Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers University, 160 Frelinghuysen Road, Piscataway, New Jersey 08854, United States.
ACS Chem Biol. 2023 Mar 17;18(3):629-642. doi: 10.1021/acschembio.2c00934. Epub 2023 Feb 28.
Methicillin-resistant (MRSA) is a multidrug-resistant (MDR) bacterial pathogen of acute clinical significance. Resistance to current standard-of-care antibiotics, such as vancomycin and linezolid, among nosocomial and community-acquired MRSA clinical isolates is on the rise. This threat to global public health highlights the need to develop new antibiotics for the treatment of MRSA infections. Here, we describe a new benzamide FtsZ inhibitor (TXH9179) with superior antistaphylococcal activity relative to earlier-generation benzamides like PC190723 and TXA707. TXH9179 was found to be 4-fold more potent than TXA707 against a library of 55 methicillin-sensitive (MSSA) and MRSA clinical isolates, including MRSA isolates resistant to vancomycin and linezolid. TXH9179 was also associated with a lower frequency of resistance relative to TXA707 in all but one of the MSSA and MRSA isolates examined, with the observed resistance being due to mutations in the gene. TXH9179 induced changes in MRSA cell morphology, cell division, and FtsZ localization are fully consistent with its actions as a FtsZ inhibitor. Crystallographic studies demonstrate the direct interaction of TXH9179 with FtsZ (SaFtsZ), while delineating the key molecular contacts that drive complex formation. TXH9179 was not associated with any mammalian cytotoxicity, even at a concentration 10-fold greater than that producing antistaphylococcal activity. In serum, the carboxamide prodrug of TXH9179 (TXH1033) is rapidly hydrolyzed to TXH9179 by serum acetylcholinesterases. Significantly, both intravenously and orally administered TXH1033 exhibited enhanced in vivo efficacy relative to the carboxamide prodrug of TXA707 (TXA709) in treating a mouse model of systemic (peritonitis) MRSA infection. Viewed as a whole, our results highlight TXH9179 as a promising new benzamide FtsZ inhibitor worthy of further development.
耐甲氧西林金黄色葡萄球菌（MRSA）是一种具有严重临床意义的多药耐药（MDR）细菌病原体。耐万古霉素和利奈唑胺等当前标准治疗抗生素的医院获得性和社区获得性 MRSA 临床分离株的耐药性正在上升。这一全球公共卫生威胁凸显了开发新抗生素治疗 MRSA 感染的必要性。在这里，我们描述了一种新的苯甲酰胺 FtsZ 抑制剂（TXH9179），与早期一代苯甲酰胺（如 PC190723 和 TXA707）相比，对金黄色葡萄球菌具有更好的抗菌活性。TXH9179 对 55 株甲氧西林敏感金黄色葡萄球菌（MSSA）和 MRSA 临床分离株的文库的抑制活性比 TXA707 强 4 倍，包括对万古霉素和利奈唑胺耐药的 MRSA 分离株。除了一个 MSSA 和 MRSA 分离株外，TXH9179 与 TXA707 相比，其耐药性发生的频率较低，观察到的耐药性是由于基因中的突变引起的。TXH9179 诱导的 MRSA 细胞形态、细胞分裂和 FtsZ 定位的变化与作为 FtsZ 抑制剂的作用完全一致。晶体学研究表明，TXH9179 与 FtsZ（SaFtsZ）直接相互作用，同时描绘了驱动复合物形成的关键分子接触。TXH9179 即使在产生抗葡萄球菌活性的浓度 10 倍以上的情况下，也不会引起任何哺乳动物细胞毒性。在血清中，TXH9179 的羧酰胺前药（TXH1033）被血清乙酰胆碱酯酶迅速水解为 TXH9179。重要的是，TXH1033 静脉内和口服给药在治疗全身性（腹膜炎）MRSA 感染的小鼠模型中均表现出比 TXA707 的羧酰胺前药（TXA709）更高的体内疗效。总的来说，我们的结果强调了 TXH9179 作为一种有前途的新苯甲酰胺 FtsZ 抑制剂，值得进一步开发。
