Repurposing Peptidomimetic as Potential Inhibitor of New Delhi Metallo-β-lactamases in Gram-Negative Bacteria

Abstract

The emergence, prevalence, and rapid spread of New Delhi metallo-β-lactamases (NDMs) in Gram-negative pathogens threaten our traditional regimen to treat bacterial infectious diseases. Discovery of novel NDMs inhibitors offers an alternative approach to restore the carbapenems activity. However, thus far, no clinical inhibitor of NDMs has been approved. In this study, the potential of peptides and analogues as carbapenems adjuvant in NDMs-positive pathogens was investigated. Herein, we successfully found that peptidomimetic 4 (PEP4) is a potential inhibitor of NDM enzymes. PEP4 displayed significant synergistic activity with Meropenem against NDM-expression Gram-negative bacteria in vitro. Moreover, PEP4 effectively restored Meropenem efficacy in mice infection models infected with NDM-5-positive E. coli. These data demonstrated the high potential of PEP4 as carbapenems adjuvant to address NDMs-positive Gram-negative pathogens.