Duda Addison M, Ma Helena R, Villalobos César A, Kuhn Sophia A, Angle Sarah S, He Katherine, Jackson Abigail C, Suh Christine M, Puccio Elena A, Anderson Deverick J, Fowler Vance G, You Lingchong, Franz Katherine J
Department of Chemistry, Duke University, Durham, North Carolina 27708, United States.
Department of Biomedical Engineering, Duke University, Durham, North Carolina 27708, United States.
ACS Infect Dis. 2025 Jul 11;11(7):1956-1967. doi: 10.1021/acsinfecdis.5c00179. Epub 2025 Jun 12.
The rise of β-lactam resistance necessitates new strategies to combat bacterial infections. We purposefully engineered the β-lactam prodrug AcephPT to exploit β-lactamase activity to selectively suppress resistant bacteria producing extended-spectrum-β-lactamases (ESBLs). Selective targeting of resistant bacteria requires avoiding interaction with penicillin-binding proteins, the conventional targets of β-lactam antibiotics, while maintaining recognition by ESBLs to activate AcephPT only in resistant cells. We show that AcephPT selectively suppresses Gram-negative ESBL-producing bacteria in clonal populations and in mixed microbial cultures, with effective selectivity for both lab strains and clinical isolates expressing ESBLs. Time-course NMR experiments confirm the hydrolytic activation of AcephPT exclusively by ESBL-producing bacteria. In mixed microbial cultures, AcephPT suppresses proliferation of an ESBL-producing strain while sustaining growth of β-lactamase-nonproducing bacteria, highlighting its potential to combat β-lactam resistance while promoting antimicrobial stewardship.
β-内酰胺耐药性的上升使得对抗细菌感染需要新的策略。我们特意设计了β-内酰胺前药AcephPT，以利用β-内酰胺酶的活性来选择性地抑制产生超广谱β-内酰胺酶（ESBLs）的耐药细菌。对耐药细菌的选择性靶向需要避免与β-内酰胺抗生素的传统靶点青霉素结合蛋白相互作用，同时保持被ESBLs识别，以便仅在耐药细胞中激活AcephPT。我们表明，AcephPT在克隆群体和混合微生物培养物中选择性地抑制产革兰氏阴性ESBLs的细菌，对表达ESBLs的实验室菌株和临床分离株均具有有效的选择性。时间进程核磁共振实验证实AcephPT仅由产ESBLs的细菌进行水解激活。在混合微生物培养物中，AcephPT抑制产ESBLs菌株的增殖，同时维持不产β-内酰胺酶细菌的生长，突出了其在对抗β-内酰胺耐药性同时促进抗菌药物管理的潜力。
