Authors: Benjamin Havenga and Wesaal Khan
Department of Microbiology, Faculty of Science, Stellenbosch University, Stellenbosch, South Africa
E-mails: email@example.com; firstname.lastname@example.org
Reviewers: Gabriela Jorge Da Silva1 and Laurent Poirel2
1Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal (E-mail: email@example.com)
2Department of Medicine, University of Fribourg, Fribourg, Switzerland (E-mail: firstname.lastname@example.org)
Ampicillin-sulbactam, imipenem-cilastatin, meropenem, doripenem, amikacin, tobramycin, tigecycline, minocycline, doxycycline, polymyxin E (colistin) and polymyxin B, are generally used for the treatment of A. baumannii infections (Vázquez-López et al., 2020). Yet, fewer effective antibiotic options are practically available as the trends of antibiotic resistance continue to rise among clinical isolates of A. baumannii. In fact, this opportunistic pathogen exhibits intrinsic resistance to several antibiotics (ampicillin, amoxicillin, aztreonam, ertapenem, trimethoprim, chloramphenicol and fosfomycin) (Clinical and Laboratory Standards Institute, 2021) and can accumulate acquired resistance to additional antibiotics (such as β-lactams, aminoglycosides, quinolones, tetracycline, and polymyxins), through vertical acquisition of chromosomal mutations or horizontal gene transfer (Lee et al., 2017). Currently, more A. baumannii strains are turning into multidrug-resistant (MDR), defined as non-susceptible to at least one agent in three or more antimicrobial classes (aminoglycosides, carbapenems, fluoroquinolones, penicillins + β-lactamase inhibitors, extended-spectrum cephalosporins, folate pathway inhibitors, penicillins + β-lactamase inhibitors, polymyxins and tetracyclines), extensively drug-resistant (XDR), defined as non-susceptible to at least one agent in all but two or fewer antimicrobial categories, or pandrug-resistant (PDR), defined as non-susceptible to any agent in all antimicrobial categories (Magiorakos et al., 2011). Such MDR, XDR and PDR strains of A. baumannii employ a variety of enzymatic and non-enzymatic mechanisms to facilitate resistance to antibiotics (Table 1 and Figure 1).
Figure 1. Primary Acinetobacter baumannii antibiotic resistance mechanisms. A) non-enzymatic resistance mechanisms, including efflux pumps such as the outer membrane porin (OMP), small multidrug resistance (SMR), major facilitator super family (MFS), multiple antibiotic and toxin extrusion (MATE) and resistance-nodulation-division (RND); B) enzymatic resistance mechanisms e.g., Ambler class A, B, C and D; C) Alteration of target sites such as DNA topoisomerase, gyrase and ribosomal protection proteins (RPPS) (Adapted from Abdi et al., 2020 and Kyriakidis et al., 2021).
Production of β-lactamases is the main mechanism of resistance to β-lactams and the most prevalent enzymatic antibiotic resistance mechanism employed by A. baumannii (Bush, 2018), where members of all the four Ambler classes (A, B, C and D) (Table 1) have been detected (Lowe et al., 2018). Inherent to all A. baumannii is the Ambler class C (AmpC) cephalosporinase encoded by the ampC gene (Bou & Martínez-Beltrán, 2000). Increased expression of ampC, conferring resistance to broad-spectrum third generation cephalosporins (e.g., ceftazidime and cefotaxime), is mainly mediated by the acquisition of an upstream insertion sequence (IS) element known as ISAba1 (Héritier et al., 2006; Karah et al., 2017). Some variants of the AmpC cephalosporinase, known as Acinetobacter-derived cephalosporinase (ADC), can also facilitate resistance to penicillins, extended-spectrum cephalosporins (cefepime), monobactam (aztreonam) and β-lactamase inhibitors (sulbactam) (Rodríguez-Martínez et al., 2010; Ingti et al., 2020) (Table 1). Apart from the inherent AmpC cephalosporinase, all A. baumannii isolates possess an intrinsic gene encoding an Ambler class D oxacillinase-51-like (OXA-51) enzyme (Héritier et al., 2005; Peleg et al., 2008). OXA-51-like is capable of hydrolyzing penicillins (benzylpenicillin, ampicillin, ticarcillin and piperacillin) and carbapenems (imipenem and meropenem), usually at low levels, when the corresponding gene is overexpressed (Figueiredo et al., 2009a; Figueiredo et al., 2009b; Gordon & Wareham, 2010). Additionally, more than 400 non-intrinsic or acquired oxacillinase enzymes have so far been identified in A. baumannii; of which those who possess carbapenemase activities have currently been clustered into five subgroups: OXA-23, OXA-40, OXA-58, OXA-143 and OXA-235 (Higgins et al., 2013) (Table 1). These carbapenem-hydrolyzing class D β-lactamases (CHDLs) hydrolyze penicillins at high level, and carbapenems weakly. Conversely, they do not significantly hydrolyze broad-spectrum cephalosporins.
Production of aminoglycoside modifying enzymes (AMEs) is the main aminoglycoside resistance mechanism in A. baumannii (Kishk et al., 2021). Based on their mode of action, AMEs have been divided into three groups, the acetyltransferases (AACs), nucleotidyltransferases (ANTs) and phosphotransferases (APHs) (Ramirez & Tolmasky, 2010) (Table 1). Sheikhalizadeh et al. (2017) detected AMEs (ANT, APH and AAC) amongst 94% (n = 89/94) of clinically derived A. baumannii, with ant(2’)-Ia conferring non-susceptibility to tobramycin, kanamycin, amikacin, gentamicin; aph(3’)-VIa conferring non-susceptibility to amikacin and tobramycin; aac(3’)-Ia conferring non-susceptibility to amikacin and tobramycin; and aac(3’)IIa conferring non-susceptibility to kanamycin (Table 1). More recently, Chen et al. (2022) detected the aph(3’)-I, ant(3″)-I and aac(6')-Ib genes amongst 86.32%, 30.53%, and 26.32% A. baumannii strains (n = 92) isolated from an intensive care unit in China. In addition to the above-mentioned enzymatic mechanisms, ribosomal modification (mediated by 16S rRNA methylases or RMTases) and overexpression of efflux pumps [resistance-nodulation-division (RND) or multiple antibiotic and toxin extrusion (MATE) superfamily] have also been associated with aminoglycoside (amikacin, gentamicin, kanamycin, and tobramycin) resistance in A. baumannii (Jouybari et al., 2021) (Table 1 and Figure 1). Currently, the increasing occurrence of acquired RMTases, leading to pan-aminoglycoside resistance, is a concerning phenomenon in A. baumannii and to date 11 RMTases genes have been detected, including armA, rmtA to rmtH, npmA and npmB, with the armA gene being the most prevalent amongst A. baumannii (Taylor et al., 2022).
Quinolone resistance in A. baumannii is primarily mediated by mutations in the quinolone resistance-determining regions of the DNA gyrase subunit A (gyrA) and topoisomerase IV subunit A (parC) genes (Figure 1) (Vila et al., 1995; Vila et al., 1997). In general, a double mutation in both gyrA and parC is needed to acquire high-levels of quinolone resistance (Vila et al., 1997; Hamouda & Amyes, 2004). A. baumannii isolates with triple mutations, involving the gyrA, gyrB and parC genes, exhibit higher ciprofloxacin resistance in comparison to isolates with double mutations in gyrA and parC (Park et al., 2011). Apart from this stepwise target modification mechanism mediated by gyrA, gyrB and parC mutations, efflux systems [RND (including AdeABC, AdeFGH and AdeIJK), MATE or Small Multidrug Resistance (SMR)] have also been associated with quinolone resistance in this pathogen (Yoon et al., 2013; Lee et al., 2017) (Table 1 and Figure 1). The AbeM pump (H+-coupled pump), belonging to the MATE family transporters, has been detected amongst A. baumannii isolates, contributing to quinolone, gentamycin, kanamycin, erythromycin, chloramphenicol, and trimethoprim resistance (Su et al., 2005). The novel SMR efflux system AbeS has also been shown to contribute to quinolone (ciprofloxacin and norfloxacin) resistance in A. baumannii, including the extensively characterised A. baumannii AYE reference strain (Srinivasan et al., 2009).
Tetracycline resistance is primarily facilitated through three main mechanisms, namely efflux pumps, enzyme inactivation and ribosomal protection proteins (RPPs) (Figure 1) (Gordon & Wareham, 2010). The major facilitator super family (MFS) and RND efflux pump systems have been associated with tetracycline resistance (Figure 1). TetA and TetB (MFS family) have frequently been detected in A. baumannii, conferring resistance to tetracycline, doxycycline, and minocycline (Wang et al., 2017) (Table 1). The RND family, including AdeABC and AdeIJK, have also been observed to contribute to tetracycline and glycylcycline (tigecycline) resistance in A. baumannii (Foong et al., 2020). In addition, a synergistic interaction between TetA and the RND-type transporters AdeABC and/or AdeIJK, resulting in higher tetracycline resistance, was reported in the A. baumannii reference strain AYE (Foong et al., 2020). Tetracycline resistance via ribosomal protection, mediated by Tet(M), was also detected in one A. baumannii clinical isolate (Ribera et al., 2003). He et al. (2019) reported on the detection and identification of two plasmid-mediated tigecycline resistance genes, tet(X3) and tet(X4), in various Enterobacteriaceae spp. as well as in A. baumannii (Table 1). Subsequently, Wang et al., (2019) investigated the occurrence of the plasmid-mediated tigecycline resistance genes in clinical A. baumannii isolates (n = 71), resulting in the detection of the novel plasmid-mediated tet(X5) gene. In addition, A. baumannii has been found to harbor the tet(X6) gene, which was detected in strains collected from humans and animal samples in both China and Taiwan (Chen et al., 2021; Hsieh et al., 2021).
The global emergence of MDR A. baumannii has led to a resurgence in the use of last-resort antibiotics, including polymyxin B and colistin (polymyxin E) (Chen et al., 2019). Polymyxins are usually used as a second line only to treat infections caused by MDR Gram-negative bacteria, such as carbapenem-resistant Enterobacterales, Pseudomonas aeruginosa and A. baumannii (Ledger et al., 2022; Paul et al., 2022). In contrast, they have been extensively used in veterinary medicine for treatment and prevention of infectious diseases and as growth promoters (Poirel et al., 2017). Polymyxins destabilize and disrupt both the outer and cytoplasmic membranes of bacterial cells via direct interaction with the negatively charged phosphate groups of the lipid A component of lipopolysaccharide (LPS) (Chamoun et al., 2021; Ledger et al., 2022). Polymyxin resistance in A. baumannii is mediated by a number of chromosomal and plasmid encoded mechanisms, which can be grouped into: (1) LPS modification; (2) LPS loss (quantitative modification); (3) reduced expression of cofactors involved in LPS synthesis; and (4) downregulation of proteins involved in the export and/or stabilisation of outer membrane precursors (Lima et al., 2018) (Table 1).
LPS modification and LPS loss have been described as the two major mechanisms of polymyxin B and colistin resistance amongst A. baumannii isolates. LPS modification involves mutations in the pmrA and pmrB genes (coding for the PmrAB two-component system), which results in the upregulation and overexpression of the pmrC gene (coding for a pEtN transferase), leading to the addition of phosphoethanolamine (pEtN) to lipid A (Charretier et al., 2018). Additionally, the insertion of ISAba1 upstream of eptA (coding for an alternative PmrC-homolog pEtN transferase) and naxD (encoding an acetyl-galactosamine deacetylase) can cause modification of lipid A and confer colistin resistance in A. baumannii (Lesho et al., 2013; Trebosc et al., 2019; Jovčić et al., 2021). Overexpression of NaxD (acetyl-galactosamine deacetylase), another LPS modifying enzyme regulated by the sensor kinase PmrB, has also been reported to confer colistin resistance (Chin et al., 2015). LPS loss involves mutations in the lipid A biosynthesis genes (Moffatt et al., 2010). Mutations in the lpxA, lpxC, and lpxD genes, or the insertion of ISAba11 in either lpxA or lpxC, have been associated with the complete loss of the LPS (Moffatt et al., 2011; Thi Khanh Nhu et al., 2016; Jovčić et al., 2021).
While colistin resistance was originally related to chromosomal mutations, limiting rapid dissemination (Thi Khanh Nhu et al., 2016), four mobile colistin resistance (mcr) genes, namely mcr-1, mcr-2, mcr-3, and mcr-4.3, have recently been detected in A. baumannii (Khuntayaporn et al., 2022). The mcr genes encode for additional pEtN transferases that can also confer colistin resistance via the addition of pEtN to lipid A (Lima et al., 2018). The mcr-1 gene was detected in one
A. baumannii clinical isolate from Pakistan (Hameed et al., 2019; GenBank accession: MK340994.1). A recent study from Iraq reported on the detection of mcr-1, mcr-2 and mcr-3 among 89, 78 and 82 isolates, respectively, including 66 isolates carrying all the three genes (Al-Kadmy et al., 2020). The mrc-1 gene was also detected in 22 isolates collected from Iraqi hospital settings during 2014 – 2018 (Kareem, 2020). None of the isolates carried mcr-2, mcr-3 or mcr-4 in the latter study. Similarly, mcr-1 was detected in two clinical isolates from Egypt (Shabban et al., 2020), while mcr-1 was reported in one isolate from China (Fan et al., 2020) and three clinical isolates from Pakistan (Ejaz et al., 2021). The mcr-4.3 gene was detected on a plasmid of 25,602 bp (pAB18PR065; GenBank accession: MK360916.1) in an A. baumannii strain isolated from pig fecal sample in China (Ma et al., 2019). Martins-Sorenson et al. (2020) detected the mcr-4.3 gene in a clinical A. baumannii isolate (597A) where it was mediated on plasmid pAb-MCR4.3 (35,502 bp; GenBank accession: CP033872.1). Plasmids pEH_mcr4.3 (18,786-bp; GenBank: CP038261.1) and pEC_mcr4.3 (43,093-bp; GenBank: CP038265.1) were detected in two A. baumannii isolates of human and food origin from the Czech Republic (Bitar et al., 2019). Later, one A. baumannii isolate obtained from frog legs was also found to carry the mcr-4.3 gene (Kalová et al., 2021).
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