An engineered prodrug selectively suppresses β-lactam resistant bacteria in a mixed microbial setting

The rise of {beta}-lactam resistance necessitates new strategies to combat bacterial infections. We purposefully engineered the {beta}-lactam prodrug AcephPT to exploit {beta}-lactamase activity to selectively suppress resistant bacteria producing extended-spectrum-{beta}-lactamases (ESBLs). Selective targeting of resistant bacteria requires avoiding interaction with penicillin-binding proteins, the conventional targets of {beta}-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 {beta}-lactamase-non-producing bacteria, highlighting its potential to combat {beta}-lactam resistance while promoting antimicrobial stewardship. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=152 SRC="FIGDIR/small/606422v1_ufig1.gif" ALT="Figure 1"> View larger version (62K): org.highwire.dtl.DTLVardef@cd7f9aorg.highwire.dtl.DTLVardef@1747bc6org.highwire.dtl.DTLVardef@6a3419org.highwire.dtl.DTLVardef@825aa6_HPS_FORMAT_FIGEXP M_FIG C_FIG