A potential benzimidazole-derived compound, NSC348884, combats carbapenem-resistant gram-negative bacteria.

Carbapenem-resistant Acinetobacter baumannii (CRAB) has been classified by WHO as a critical-priority pathogen that poses the most serious threat to public health and urgently requires the development of novel antimicrobial agents. Here, we identified a benzimidazole analogs NSC348884 with additive or synergistic therapeutic effects against carbapenem-resistant gram-negative bacteria (CR-GNB) when combined with imipenem. Further investigation found that NSC348884 exhibited direct antibacterial efficacy without inducing resistance, and comparable anti-biofilm activity to polymyxin B (PMB) against CRAB. Mechanistically, metabolomic and transcriptomic analysis demonstrated that NSC348884 perturbed lipid metabolic homeostasis and disrupted membrane integrity, which induced reactive oxygen species (ROS) burst and finally led to growth inhibition and bacterial death. In a mouse model of systemic CRAB infection, NSC348884 decreased the blood bacterial load and protected against lung injury and inflammation. Together, these results demonstrate that NSC348884 is a promising drug candidate and provide a basis for the development and clinical application of NSC348884 for the treatment of CRAB infection.