Polymyxin resistance in Gram-negative bacteria: a comprehensive review with a focus on the role of 4-amino-4-doexy-L-arabinose.

Polymyxin resistance among Gram-negative bacteria poses a serious global health threat by limiting treatment options for multidrug-resistant (MDR) infections. This review summarizes current knowledge on the molecular mechanisms underlying polymyxin resistance, with a particular focus on the role of 4-amino-4-deoxy-L-arabinose (L-Ara4N) in lipopolysaccharide (LPS) modification. We discuss the regulation of L-Ara4N biosynthesis and transfer by two-component systems such as PmrAB, PhoPQ, CrrAB, CprRS, ColRS, and ParRS, which mediate bacterial responses to environmental stimuli. Furthermore, we synthesize recent findings on combination therapies designed to restore polymyxin efficacy, including agents such as natural polyphenols, antimicrobial peptides, and secondary metabolites. Special attention is given to emerging strategies targeting ArnT, including inhibitors with ent-beyerane skeletons (e.g., BBN149 from Fabiana densa var. ramulosa). Finally, this review highlights ongoing challenges related to polymyxin toxicity and underscores the need for future research aimed at optimizing dosing strategies and reducing adverse effects. By integrating findings across multiple studies, this review provides an updated overview of current approaches to counteract polymyxin resistance in Gram-negative bacteria.