Colistin Resistance Mechanism and Management Strategies of Colistin-Resistant Acinetobacter baumannii Infections

Abstract

The emergence of antibiotic-resistant Acinetobacter baumannii (A. baumannii) is a pressing threat in clinical settings. Colistin is currently a widely used treatment for multidrug-resistant A. baumannii, serving as the last line of defense. However, reports of colistin-resistant strains of A. baumannii have emerged, underscoring the urgent need to develop alternative medications to combat these serious pathogens. To resist colistin, A. baumannii has developed several mechanisms. These include the loss of outer membrane lipopolysaccharides (LPSs) due to mutation of LPS biosynthetic genes, modification of lipid A (a constituent of LPSs) structure through the addition of phosphoethanolamine (PEtN) moieties to the lipid A component by overexpression of chromosomal pmrCAB operon genes and eptA gene, or acquisition of plasmid-encoded mcr genes through horizontal gene transfer. Other resistance mechanisms involve alterations of outer membrane permeability through porins, the expulsion of colistin by efflux pumps, and heteroresistance. In response to the rising threat of colistin-resistant A. baumannii, researchers have developed various treatment strategies, including antibiotic combination therapy, adjuvants to potentiate antibiotic activity, repurposing existing drugs, antimicrobial peptides, nanotechnology, photodynamic therapy, CRISPR/Cas, and phage therapy. While many of these strategies have shown promise in vitro and in vivo, further clinical trials are necessary to ensure their efficacy and widen their clinical applications. Ongoing research is essential for identifying the most effective therapeutic strategies to manage colistin-resistant A. baumannii. This review explores the genetic mechanisms underlying colistin resistance and assesses potential treatment options for this challenging pathogen.

Keywords: A. baumannii; antibiotic-resistant; colistin; lipid A; mutation.

Figure 1

Mechanisms of action of colistin against A. baumannii. Positively charged colistin interacts with the negatively charged phosphate groups of lipid A, displacing Ca²⁺ and Mg²⁺ ions, leading to membrane disruption [37]. By binding to LPS, colistin neutralizes LPS endotoxin activity [39]. Additionally, colistin induces intracellular ROS accumulation, which is converted to H₂O₂ by superoxide dismutase. H₂O₂ participates in the Fenton reaction, oxidizing Fe²⁺ to Fe³⁺ and generating hydroxyl radicals (•OH) that disrupt iron homeostasis, causing oxidative damage to DNA and membrane lipids [40] (created with Biorender.com accessed at 29 October 2024). + represent the positive charge of colistin.

Figure 2

A schematic illustration showing the general mechanisms of colistin resistance in A. baumannii. (A) Colistin resistance occurs due to modification in lipid A of lipopolysaccharides (LPSs), reducing its negative charge and interfering with colistin binding. The PmrA/PmrB system controls the pmrC gene, which encodes phosphoethanolamine transferase adding phosphoethanolamine (PEtN) to lipid A. Plasmid-borne mcr genes also produce enzymes with this function. Mutations in PmrB can activate the naxD gene, modifying lipid A by adding galactosamine (GalN). Overexpression of eptA, often triggered by insertion sequences like ISAba1, also contributes to resistance. (B) Overexpression of the emrAB efflux pump expels colistin from the membrane. (C) Mutations or disruptions in lipid A biosynthesis genes lpxA, lpxC, or lpxD, cause LPS deficiency, leading to resistance (created with Biorender.com accessed at 22 November 2024).PmrB* means activated pmrB which phosphorylates the pmrA and increase the expression of pmrC.