Effects of In Vitro Combination Therapy with Polymyxin B on Delaying Resistance in Klebsiella pneumoniae and Insights into the Mechanisms of Polymyxin-Induced Resistance

• DOI: 10.1016/j.jgar.2025.04.009
• Publication Date: 2025-04-29T16:08:12Z
• Authors: Huanhuan Zhang; Wei Feng; Fengjun Sun; Te Xu; Yan Qian
• Keywords: Polymyxin; Polymyxin B; Klebsiella; Combination therapy

This study aimed to investigate the effects of polymyxin B (PMB) in combination with other antibiotics on delaying resistance Klebsiella pneumoniae and explore mechanisms underlying PMB-induced resistance. In vitro continuous induction experiments were performed observe changes drug susceptibility PMB alone versus combination. RNA-seq, qRT-PCR, proteomic analyses utilized evaluate differential gene protein expression between induced-resistant strains those exhibiting delayed Then, knockout validate functional roles relevant genes. These findings indicated that could induce within 1-2 days, whereas amikacin or tigecycline onset by 6 days. revealed significant upregulation nlpE, two-component systems AcrAB-TolC efflux pump-associated genes resistant strains, these downregulated combined amikacin. Deletion complementation demonstrated levels pump-related nlpE strains. Furthermore, a PmrA, PhoP, PhoQ, PagP, AcrB proteins associated cationic antimicrobial peptide pathways wild-type complemented no change was observed strain. contributes modulating pump PhoP/Q PmrA/B systems. The use effectively delays development K. through regulation its signaling pathways.