Abstract
AbstractThe 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. Computational approaches provide a rationale for structural modifications to the prodrug to achieve this biased activity. We show 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 hydrolytic activation of AcephPT exclusively by ESBL-producing bacteria. In mixed microbial cultures, AcephPT suppresses proliferation of ESBL-producing strains while sustaining growth of β-lactamase-non-producing bacteria, highlighting its potential to combat β-lactam resistance while promoting antimicrobial stewardship.Abstract Figure
Publisher
Cold Spring Harbor Laboratory
Reference38 articles.
1. β-Lactams and β-Lactamase Inhibitors: An Overview
2. Epidemiology of β-Lactamase-Producing Pathogens
3. ; for the Antibacterial Resistance Leadership Group;Confronting Antimicrobial Resistance Together. Am. J. Physiol. Lung Cell Mol,2022
4. Centers for Disease Control and Prevention (U.S.). Antibiotic Resistance Threats in the United States, 2019; Centers for Disease Control and Prevention (U.S.), 2019.
5. Global Burden of Bacterial Antimicrobial Resistance in 2019: A Systematic Analysis;The Lancet,2022