Enhanced meropenem activity by a microbiome derived peptide targeting oxacillinase 48 carbapenemase in carbapenem resistant Klebsiella pneumoniae isolates

Carbapenem-resistant Enterobacterales, particularly those producing oxacillinase 48 (OXA-48) carbapenemase (blaOXA−48), pose a critical global health threat, especially in the Middle East where its prevalence is remarkably high. The lack of specific OXA-48 inhibitors and the emergence of resistance even to avibactam highlight the urgent need for novel therapeutic strategies. This study investigated the peptide M104 as an adjunctive agent to meropenem against multidrug-resistant (including meropenem-resistant) blaOXA−48 positive Klebsiella pneumoniae clinical isolates. Peptide M104 at the concentration of 125 µg/mL enhanced meropenem’s antibacterial activity against all ten tested blaOXA−48 positive isolates and significantly reduced the meropenem minimum inhibitory concentration (MIC) values at least two-fold for all ten clinical isolates (p-value < 0.002). This enhancement was not observed in blaOXA−48 negative isolates, and the peptide showed no intrinsic antibacterial activity. In strong biofilm-forming isolates, M104 reduced meropenem’s minimum biofilm inhibitory concentrations (MBIC) by two-fold, although this reduction was not statistically significant (p-value = 0.06), and showed limited meropenem enhancement in reducing minimum biofilm eradication concentration (MBEC). Cytotoxicity assays revealed that M104 at 200 µg/mL did not reduce HDFa cell viability after 24 h, and the peptide also showed no hemolytic activity at this concentration. These findings suggest peptide M104 is a candidate OXA-48 inhibitor, capable of enhancing meropenem’s efficacy against carbapenem-resistant K. pneumoniae infections, while showing limited cytotoxicity and no hemolytic effects. Further validation using a larger number of clinical isolates and in vivo studies is needed to confirm these results and support peptide M104 as the first peptide inhibitor of OXA-48 carbapenemase.