Citation: Novovi´ c, K.; Jovˇ ci´ c, B. Colistin Resistance in Acinetobacter baumannii: Molecular Mechanisms and Epidemiology. Antibiotics 2023, 12, 516. https://doi.org/10.3390/ antibiotics12030516 Academic Editor: Ilias Karaiskos Received: 26 January 2023 Revised: 17 February 2023 Accepted: 2 March 2023 Published: 4 March 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). antibiotics Review Colistin Resistance in Acinetobacter baumannii: Molecular Mechanisms and Epidemiology Katarina Novovi´ c 1 and Branko Jovˇ ci´ c 1,2, * 1 Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 11042 Belgrade, Serbia 2 Faculty of Biology, University of Belgrade, Studentski Trg 16, 11000 Belgrade, Serbia * Correspondence: bjovcic@bio.bg.ac.rs Abstract: Acinetobacter baumannii is recognized as a clinically significant pathogen causing a wide spectrum of nosocomial infections. Colistin was considered a last-resort antibiotic for the treatment of infections caused by multidrug-resistant A. baumannii. Since the reintroduction of colistin, a number of mechanisms of colistin resistance in A. baumannii have been reported, including complete loss of LPS by inactivation of the biosynthetic pathway, modifications of target LPS driven by the addition of phosphoethanolamine (PEtN) moieties to lipid A mediated by the chromosomal pmrCAB operon and eptA gene-encoded enzymes or plasmid-encoded mcr genes and efflux of colistin from the cell. In addition to resistance to colistin, widespread heteroresistance is another feature of A. baumannii that leads to colistin treatment failure. This review aims to present a critical assessment of relevant published (>50 experimental papers) up-to-date knowledge on the molecular mechanisms of colistin resistance in A. baumannii with a detailed review of implicated mutations and the global distribution of colistin-resistant strains. Keywords: Acinetobacter baumannii; colistin resistance; lpx; pmr; mcr; LPS; lipid A; phosphoethanolamine transferase; epidemiology 1. Introduction Colistin (polymyxin E) is a nonribosomally synthesized polycationic peptide that be- longs to the class of polymyxin antibiotics, of which only two are used clinically: polymyxin B and colistin [1]. Colistin was introduced into clinical practice in the 1950s, but its use in human medicine was mainly limited to the treatment of pulmonary infections caused by multidrug-resistant (MDR) Gram-negative pathogens in patients with cystic fibrosis due to nephrotoxicity and neurotoxicity [2,3]. However, the widespread use of colistin in animal feed production has been maintained in developing countries and poses a major public health risk [4]. The rise of MDR, extensively drug-resistant (XDR), and pan drug-resistant (PDR) strains of Gram-negative bacteria has sparked interest in the revival of antibiotics, such as colistin, which can be used as a last resort [5–7]. Colistin is a mixture of the cyclic decapeptide colistin A and B with a fatty acid chain (6-methyl-octanoic acid in colistin A or 6-methyl-heptanoic acid in colistin B) linked by an alpha-amide bond. The amphiphilic surfaces of colistin, which allow detergent-like activity on bacterial membranes, are formed by the N-terminal fatty acyl chain, D-Leu-Leu (hydrophobic), and three cationic amino acids (hydrophilic) [8,9]. Two forms, colistin sulfate for oral administration and colistimethate sodium for parenteral formulations, are currently commercially available. Colistin is positively charged, therefore, it interacts electrostatically with the negatively charged phosphate groups of lipid A, the lipopolysaccharide (LPS) component of Gram- negative bacilli outer membrane [10]. After the initial interaction, colistin displaces the divalent calcium and magnesium cations that affect the three-dimensional structure of Antibiotics 2023, 12, 516. https://doi.org/10.3390/antibiotics12030516 https://www.mdpi.com/journal/antibiotics