An Engineered Prodrug Selectively Suppresses β-Lactam-Resistant Bacteria in a Mixed Microbial Setting.

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.

Duke Scholars

Author Katherine J. Franz Chemistry

Author Deverick John Anderson Medicine, Infectious Diseases

Author Lingchong You Biomedical Engineering

Author Vance Garrison Fowler Jr. Medicine, Infectious Diseases

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