The global rise in antibiotic resistance in bacteria poses a major challenge in treating infectious diseases. Polymyxins (e.g., polymyxin B and colistin) are last-resort antibiotics against resistant Gram-negative bacteria, but the effectiveness of polymyxins is decreasing due to widespread resistance among clinical isolates. The aim of this literature review was to decipher the evolving mechanisms of resistance to polymyxins among pathogens of clinical significance. We deciphered the molecular determinants of polymyxin resistance, including distinct intrinsic molecular pathways of resistance as well as evolutionary characteristics of mobile colistin resistance. Among clinical isolates, Acinetobacter stains represent a diversified evolution of resistance, with distinct molecular mechanisms of intrinsic resistance including naxD, lpxACD, and stkR gene deletion. On the other hand, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa are usually resistant via the PhoP-PhoQ and PmrA-PmrB pathways. Molecular evolutionary analysis of mcr genes was undertaken to show relative relatedness across the ten main lineages. Understanding the molecular determinants of resistance to polymyxins may help develop suitable and effective methods for detecting polymyxin resistance determinants and the development of novel antimicrobial molecules.

Background: Carbapenem-resistant Acinetobacter baumannii is a critical priority pathogen of the Acinetobacter calcoaceticus-Acinetobacter baumannii Complex (Acb Complex) characterized by extensive multidrug resistance, leading to increased reliance on last-line polymyxins and widespread use of cationic disinfectants in healthcare settings. However, shared membrane-targeting mechanisms raise concerns regarding potential cross-resistance between disinfectants, polymyxins, and cationic antimicrobial peptides. Methods: A diverse panel of clinical A. baumannii isolates from Australia (n = 9), Pakistan (n = 15), and Switzerland (n = 3), and standard strains (n = 3), including polymyxin-resistant laboratory and clinical mutant strains (n = 4), was used. Minimum inhibitory concentrations (MICs) of polymyxin B, colistin, three cationic disinfectants (polyquaternium-1; PQ-1), polyhexamethylene biguanide (PHMB), and chlorhexidine (CHX), and four Antimicrobial peptides (AMPS: LL-37, melimine, Mel4, and lactoferricin) were determined using broth microdilution. Correlations between MICs were assessed using Spearman analysis, and differences between polymyxin-resistant and -susceptible isolates were analyzed statistically. Results: Most isolates were susceptible to polymyxins. The MIC data confirmed that one mutant strain, A. baumannii 19606 (R), and three clinical isolates displayed high-level polymyxin B and colistin resistance. PQ-1 exhibited the greatest antibacterial activity among disinfectants, while LL-37 showed the lowest and most consistent MICs among AMPs; lactoferricin was largely inactive. Within this exploratory strain collection, polymyxin-resistant isolates exhibited lower MICs to PQ-1 and PHMB, indicating collateral susceptibility. Correlation analysis revealed significant negative correlations between polymyxin susceptibility and disinfectant MICs (colistin–PQ-1 (r = −0.67 and p = 0.0001), colistin–PHMB (r = −0.44 and p = 0.05), and polymyxin B–PHMB (r = −0.48 and p = 0.005), whereas no consistent correlation was observed between polymyxins and AMPs, including LL-37. A moderate positive correlation was identified between colistin and Mel4 activity (r = 0.45 and p = 0.05). Conclusions: These findings indicate diverse susceptibility patterns of A. baumannii to cationic antimicrobials. Within this exploratory strain collection, polymyxin resistance was not associated with reduced susceptibility to disinfectants or most antimicrobial peptides and was instead associated with lower MICs to certain disinfectants. No evidence of cross-resistance between polymyxins and LL-37 was observed under the conditions tested, suggesting that polymyxin resistance does not necessarily confer reduced in vitro susceptibility to this host defense peptide. Given the small number of polymyxin-resistant isolates, these findings should be considered hypothesis-generating and require confirmation in larger collections of genetically characterized strains. Further mechanistic studies are needed to determine the biological basis and generalizability of these observed susceptibility patterns.