Colistin resistance in Acinetobacter baumannii

Authors: Katarina Novović1 and Branko Jovčić1,2

1 Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia

2 Faculty of Biology, University of Belgrade, Belgrade, Serbia


Reviewer: Younes Smani

Molecular Biology and Biochemical Engineering Dept., Pablo deOlavide University, Seville, Spain (

Colistin resistance in Acinetobacter baumannii

Multidrug-resistant (MDR) and extensively drug-resistant (XDR) A. baumannii are of major public health concern as they cause a high mortality rate in patients. MDR and XDR phenotypes arise from a plethora of intrinsic resistance mechanisms, dynamic gene flow and horizontal gene transfer that shape the variable, open resistome of A. baumannii (Kyriakidis et al., 2020). Colistin is considered a last-line antibiotic with significant activity against MDR and XDR strains and is used as a rescue therapy (Pormohammad et al., 2020). Due to the increasing and non-optimal use of colistin in treating infections, a rapid spread of colistin resistance in A. baumannii has been observed (Pormohammad et al., 2020, Novović and Jovčić, 2023). Published data show that the prevalence of colistin resistance is higher in Southeast Asia and Eastern Mediterranean countries than in other regions of the world, with an overall figure of 11.2% (Pormohammad et al., 2020, Novović and Jovčić, 2023).

Figure 1. Schematic representation of general mechanisms of colistin resistance in A. baumannii. (A). Addition of phosphoethanolamine (PEtN) moiety to lipid A component of LPS changes the charge of the membrane and results in repulsion of colistin and resistance. This is mostly promoted by altered PmrB histidine kinase that activates expression of the pmrCAB resulting in overexpression of the PmrC PEtN transferase. This could also be achieved by overexpression of EptA or Mcr PEtN transferases. (B). LPS deficiency mediated via the lpxACD genes inactivation results in change of the cell surface charge and repulsion of colistin, as well. (C). Efflux of colistin mediated by efflux  pumps has been described as mechanism contributing the resistance to colistin in A. baumannii.

Mechanisms of colistin resistance

The resistance of A. baumannii to colistin is essentially based on two mechanisms, which depend on the complete loss or alteration of the primary target of colistin, the lipid A component of LPS. Both mechanisms lead to a loss of colistin activity due to a decrease of negative charge on the cell surface (Olaitan et al., 2014) (Figure 1A and B). LPS deficiency results from the inactivation of genes encoding enzymes that catalyze the first steps of lipid A biosynthesis (lpxA, lpxC and lpxD genes) (Moffatt et al., 2010). Modification of LPS by the addition of phosphoethanolamine (PEtN) moieties to lipid A is by far the most common mechanism of colistin resistance in A. baumannii. Genetic determinants of this modification are either the chromosomal pmrCAB operon and eptA gene-encoded enzymes or plasmid-encoded mcr genes (Figure 1A). The amino acid changes in the proteins of the PmrAB two-component system that cause colistin resistance are very frequent and diverse, particularly in the histidine kinase A (HisKA) domain of the PmrB protein (Novović and Jovčić, 2023). These changes within the PmrAB proteins lead to overexpression of the phosphoethanolamine transferase PmrC, a key catalyst of PEtN modification of LPS (Arroyo et al., 2011). Increased expression of the eptA gene (pmrC homolog) also enables resistance of A. baumannii to colistin, but is less common (Lesho et al., 2013). Plasmid-encoded mcr genes (especially mcr-1 and mcr-4.3 variants) are the main cause of the rapid spread of resistance to colistin in A. baumannii. Colistin efflux (Figure 1C) (Lin et al., 2017), loss of non-Lpx proteins (lipoproteins) involved in outer membrane (OM) assembly and maintenance (Lima et al., 2017, Bailing et al., 2020) and Omp25 expression reduction have also been described as mechanisms of resistance to colistin (Parra Millán et al., 2018). Heteroresistance to colistin in A. baumannii is based on the same mechanisms as colistin resistance (lpxACD, pmrCAB and efflux pumps) (Novović and Jovčić, 2023).

Global epidemiology of colistin-resistant A. baumannii

The global distribution of colistin-resistant A. baumannii strains is a picture that will change in the future as we collect more and more data. However, at this stage, using the Pasteur/Oxford MLST scheme to differentiate sequence types (STs), we have identified a predominance of ST2 (Pasteur) worldwide (except Australia) and ST1 (Pasteur) in Europe and Africa, which are not only nosocomial, but also of animal origin (Novović and Jovčić, 2023) (Figure 2). A number of STs (Pasteur) could be considered exclusive to the specific regions: (i) ST195, ST345, ST490, ST492, ST537, ST632, ST636, ST745, ST1421 and ST1816 in Europe, (ii) ST1303 in Asia, (iii) ST158 and ST570 in Africa, (iv) ST46 and ST94 in North America, (v) ST15, ST25, ST79 and ST730 in South America (Novović and Jovčić, 2023) (Figure 2). The more discriminant Oxford MLST scheme showed several STs distributed over different continents, such as ST92 in Asia and North America, ST195 in Europe and Africa, ST208 and ST281 in Europe and North America, ST451 in Europe, Asia and North America (Novović and Jovčić, 2023) (Figure 2). These data indicate a remarkable distribution of colistin-resistant A. baumannii in Europe, Asia and North America.

Figure 2. Global epidemiology of colistin-resistant A. baumannii STs based on Pasteur (blue circles) and Oxford (green circles) MLST scheme. ND – no data available. STs that were found in more than one continent are within circles bigger in size.


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