一种新型KPC-2抑制剂:PHT427

PHT427 functions as a novel inhibitor of KPC-2

KPC-2型β-内酰胺酶对超广谱头孢菌素和碳青霉烯类抗生素具有耐药性,并已成为治疗革兰氏阴性菌感染的全球重大威胁,因此寻找新型抗菌剂和新的抗感染策略非常重要。我们前期经筛选发现PHT427是一种有效的NDM-1抑制剂,进一步研究发现其对KPC-2也有明显的抑制活性。结果显示PHT427能够显著抑制KPC-2,IC50值为2.04μM,并且与美罗培南联用对大肠杆菌BL21(DE3)/p ET28a(+)-bla KPC-2具有明显的协同作用。荧光淬灭和SPR结果表明PHT427能够与KPC-2发生相互作用。分子对接与定点突变的结果进一步表明Arg220、Thr235和Thr237是促进这种相互作用的关键氨基酸残基。研究表明PHT427是一种具有潜力的KPC-2抑制剂并且能够协助碳青霉烯类抗生素抑制KPC-2产生菌。

KPC-2 β-lactamases are a significant global concern as they confer resistance to extended-spectrum cephalosporins and carbapenems, thereby complicating the treatment of Gram-negative bacterial infections. This has underscored the urgent need for novel antimicrobial agents and innovative anti-infective strategies. Our prior research has identified PHT427 as a potent NDM-1 inhibitor. Subsequent investigations revealed its marked inhibitory activity against KPC-2. Specifically, PHT427 inhibited KPC-2 with an IC50 value of 2.04 μM and exhibited a synergistic effect against Escherichia coli BL21(DE3)/p ET28a(+)-bla KPC-2 when combined with meropenem. Fluorescence quenching and SPR analyses suggested a direct interaction between PHT427 and KPC-2. Molecular docking and targeted mutagenesis studies further highlighted Arg220, Thr235, and Thr237 as critical residues facilitating this interaction. In summary, our data proposed PHT427 as a promising KPC-2 inhibitor that could potentiate the efficacy of carbapenem antibiotics against KPC-2-producing bacteria.