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Review

Molecular mechanisms related to colistin resistance in Enterobacteriaceae

, , , , , , , , & show all
Pages 965-975 | Published online: 24 Apr 2019

Abstract

Colistin is an effective antibiotic for treatment of most multidrug-resistant Gram-negative bacteria. It is used currently as a last-line drug for infections due to severe Gram-negative bacteria followed by an increase in resistance among Gram-negative bacteria. Colistin resistance is considered a serious problem, due to a lack of alternative antibiotics. Some bacteria, including Pseudomonas aeruginosa, Acinetobacter baumannii, Enterobacteriaceae members, such as Escherichia coli, Salmonella spp., and Klebsiella spp. have an acquired resistance against colistin. However, other bacteria, including Serratia spp., Proteus spp. and Burkholderia spp. are naturally resistant to this antibiotic. In addition, clinicians should be alert to the possibility of colistin resistance among multidrug-resistant bacteria and development through mutation or adaptation mechanisms. Rapidly emerging bacterial resistance has made it harder for us to rely completely on the discovery of new antibiotics; therefore, we need to have logical approaches to use old antibiotics, such as colistin. This review presents current knowledge about the different mechanisms of colistin resistance.

Introduction

Antibiotic resistance, which started in the 1970s among Gram-negative bacteria, is a crucial global problem.1–Citation3 Development of antibiotic resistance is a phenomenon correlated with antibiotic overuse and bacterial evolution.Citation4 Microorganisms can use several mechanisms to adapt against antimicrobial agents and environmental stimulants. Bacteria can use genetic alterations in their genes to form genes with improved performance to overcome antibiotics. Modification in only a few base pairs in DNA causing replacement of one or a few amino acids in an important target, such as cell structure or cell wall and enzymes, leads to new resistance strains.Citation5 Initially, the problem of bacterial resistance to antibiotics was solved by the invention of the latest categories of antibiotics, including aminoglycosides, glicopeptides, and macrolides, and further by the c

hemical modification of old antibiotics. Unfortunately, these antibiotics could not keep pace with the development of antibiotic resistance in bacterial pathogens.Citation6 Mobile genes conferring resistance to aminoglycosides and broad-spectrum β-lactams can transfer between species and are one of the important factors accounting for the progressive erosion of antimicrobial activity in both hospital and community settings.Citation7 Emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Gram-negative bacteria, as well as the lack of novel agents against these pathogens, have led to the reintroduction of colistin, an old and valuable antibiotic as a last-resort treatment option.Citation8

Colistin, also known as polymyxin E, was isolated in 1947 from the bacterium Paenibacillus polymyxa subsp. colistinus.Citation9 This organism also produces colistinase, which inactivates colistin.Citation10 Colistin is a polycationic antibiotic, and has significant activity against Gram negative bacteria, such as Enterobacteriaceae. The outer cell membrane of Gram-negative bacteria is the main site of action for colistin. When colistin binds to lipopolysaccharides in the outer membrane, electrostatic interaction occurr between the α,γ-diaminobutyric acid of colistin and the phosphate groups of the lipid A region of lipopolysaccharide (LPS). It competitively displaces divalent cations (Ca2+ and Mg2+) from the phosphate groups of membrane lipids.Citation11,Citation12 Therefore, disruption of LPS may cause increased permeability of the outer membrane and leakage of intracellular contents, ultimately leading to cell death.Citation13Citation15 Unfortunately, during the last few decades, the emergence of colistin-resistant isolates has been frequently reported,Citation10,Citation12 which has increased inappropriate use of this drug, especially as monotherapy could be the cause of this problem.Citation16Citation18 In addition, there have been reports of increased infection due to bacteria with intrinsic resistance to colistin, such as Proteus spp., Providencia spp., Serratia spp., and Morganella spp.Citation19Citation21 In this article, we assess different mechanisms of colistin resistance in Enterobacteriaceae.

Activity spectrum of colistin

Colistin is a narrow-spectrum antimicrobial agent that has significant activity against most members of the Enterobacteriaceae family, including Escherichia coli, Enterobacter spp., Klebsiella spp., Citrobacter spp., Salmonella spp., and Shigella spp. It also has activity against common nonfermentative Gram-negative bacteria, such as Acinetobacter baumannii, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia.Citation14,Citation22Citation24 In addition, Haemophilus influenzae, Legionella pneumophila, Aeromonas spp., and Bordetella pertussis are naturally susceptible to colistin.Citation15,Citation22,Citation25,Citation26

Conversely, among the Enterobacteriaceae, Proteus spp. and Serratia marcescens have intrinsic resistance to colistin. On the other hand, Morganella morganii, Providencia spp., Pseudomonas mallei, Burkholderia cepacia, Chromobacterium spp., Edwardsiella spp., Brucella, Legionella, and Vibrio cholera are typically resistant to colistin. Colistin is not active against Gram-negative cocci, such as Neisseria spp., gramGram-positive bacteria, anaerobic bacteria, eukaryotic microbes, or mammalian cells.Citation14,Citation27Citation31

Mechanisms of colistin resistance in Enterobacteriaceae

Although the main mechanism of resistance to colistin is unclear, Gram-negative bacteria employ several mechanisms to protect themselves against colistin toward other polymyxins (). According to the literature, most colistin-resistance mechanisms are adaptive mechanisms ithat occur after in vitro exposure.Citation15 Resistance to colistin occur with LPS modification via different routes. The most common strategies for resistance to colistin are modifications of the bacterial outer membrane through alteration of the LPS and reduction in its negative charge.Citation32,Citation33 The other strategy is the overexpression of efflux-pump systems.Citation34 Another mechanism is overproduction of capsule polysaccharide.Citation35Citation37 No enzymatic mechanisms of resistance have been reported, but strains of P. polymyxa produce colistinase.Citation38

Figure 1 Regulation and plasmid-mediated pathways of lipopolysaccharide modifications in Enterobacteriaceae.

Figure 1 Regulation and plasmid-mediated pathways of lipopolysaccharide modifications in Enterobacteriaceae.

Intrinsic resistance mechanisms

Resistance to polymyxins occurs naturally in P. mirabilis and S. marcesens by modification of the LPS via cationic substitution. The mechanism of resistance in these species is linked to expression of the arnBCADTEF operon and the eptB gene. In this way, the 4-amino-4-deoxy-L-arabinose (L-Ara4N) and phosphoethanolamine (pEtN) cationic groups are added to the LPS by this operon and gene, respectively. It has been shown that the LPS of P. mirabilis contains L-Ara4N and the genome of this bacterium contains the eptC gene, which is mediated to the modification of LPS with PETN.Citation39Citation41 Putative loci in P. mirabilis include the sap operon encoding a transport protein, ATPase gene, and O-acetyltransferase gene, which take part in biosynthesis or transfer of amino arabinose.Citation42 Also, the existence of rppA/rppB TCS has been discovered to play a role in activation of the arnBCADTEF operon.Citation43,Citation44 Similarly, this operon is responsible for intrinsic resistance to colistin in S. marcescens, as it has been shown that arnB and arnC mutants lead to a reduction insusceptibility to colistin (minimum inhibitory concentration [MIC] from 2,048 to 2 µg/mL) compared to the wild type.Citation45

This modification of LPS and the increase inits charge give rise to the affinity of colistin decrease for binding to LPS. Therefore, intrinsic resistance has occurred in these species.Citation9,Citation41,Citation43

Acquired resistance mechanisms in Enterobacteriaceae

Acquired colistin-resistance mechanisms have been recognized in some members of Enterobacteriaceae family, such as E. coli, Salmonella spp., Klebsiella spp., and Enterobacter spp., and remain unknown for other bacterial species. Resistance mechanisms are presumed to be linked to chromosomal mutation untransferable via horizontal gene transfer.Citation46Citation48 Only one mechanism of resistance has been identified as a transferable mechanism (plasmid-mediated mcr gene) so far ().Citation9,Citation21

Table 1 Acquired and intrinsic strategies employed by Gram-negative bacteria for achieving resistance to colistin

Many genes and operons play a role in modification of LPS, which in turn leads to colistin resistance. These include: genes and operons responsible for encoding enzymes that have a direct role in LPS modification, such as the pmrC and pmrE genes and the pmrHFIJKLM operon;Citation46,Citation49 regulatory two-component systems (TCSs), including PmrAB and PhoPQ, as well as crrAB, which regulates the PmrAB system;Citation50Citation52 the mgrB gene, a negative regulator of TCSs, including PmrAB and PhoPQ;Citation53 plasmid-mediated mcr genes;Citation54,Citation55 and Cpx and Rcs as regulator of upregulation of capsule biosynthesis and activator of the efflux pump KpnEF regulating the PhoPQ system, respectively.Citation8

mgrB gene and regulators of PmrAB and PhoPQ two-component systems

Some operons and regulators have a role in the modification of LPS by PmrAB and PhoPQ TCSs. The pmrABC operon encodes PmrA (BasR) as a regulator protein, PmrB (BasS) as a cytoplasmic membrane-bound sensor kinase, and PmrC as a putative membrane protein.Citation56 The addition of L-arabinoseamine (L-Ara4N) to the 1-phosphate or 4-phosphate group leads to colistin resistance.Citation46 Generally, L-Ara4N is connected to 4-phosphate and modifies it while PETN is connected to 1-phosphate.Citation57,Citation58 The pmrHFIJKLM operon (also named arnBCDADTEF or pbgPE) and PmrE synthesize L-Ara4N from uridine diphosphate glucuronic acid and fix it to lipid A.Citation59,Citation60 The biosynthesis of L-Ara4N depends on the pmr (arn) operon.Citation61 Moreover, under environmental stimulants, such as macrophage phagosomes, the high concentration of iron (Fe3+) and exposure to aluminum (Al3+), as well as acidic pH, leads to activation of PmrB.Citation56,Citation62 On the other hand, low concentration of Mg2+ or Ca2+ leads to activation of phoQ.Citation63,Citation64 PmrB activates PmrA by phosphorylation, and PmrA in turns activates regulation of the pmrABC and pmrHFIJKLM operons and the pmrE gene. Subsequently, these operons and genes lead to LPS modification by adding PETN and L-Ara4N to lipid A.Citation56 Mutation of pmrA/pmrB results in upregulation of the pmrABC and pmrFHIJKLM operons and pmrE gene. Mutation within the pmrA and pmrB genes leading to colistin resistance has been described in Klebsiella pneumoniae and Salmonella entericca ().Citation65Citation69

On the other hand, the phoPQ TCS encodes PhoP as a regulator protein and PhoQ as a sensor kinase. Under conditions of low magnesium or calcium, acidic PH, or cationic antimicrobial peptide, PhoPQ is activated and protects bacteria.Citation21,Citation63,Citation64 Activated PhoPQ leads to modification of lipid A via two routes: PhoQ activates PhoP by its kinase activity via phosphorylation, which activates transcription of the pmrFHIJKLM operon, followed by modification of lipid A;Citation70,Citation71 and PhoP indirectly activates pmrA by bypassing the PmrD connector protein, subsequently activates the transcription of the pmrHFIJKLM operon and synthesizes PETN, which transfers it to lipid A.Citation72,Citation73

Various of PETN-coding genes, such as eptA (pmrC), eptB (pagC), and eptC (cptA), are able to add PETN to different sites of LPS.Citation74,Citation75 Mutation of the phoP/Q genes has been identified in K. pneumoniae and E. coli that led to acquired colistin resistance.Citation65,Citation67,Citation76Citation78

The mgrB gene encodes a small transmembrane protein of 47 amino acids that exerts negative feedback on the PhoPQ TCS.Citation79 This protein inhibits the kinase activity of PhoQ, which in turn represses expression of the phoQ gene. Nevertheless, mutation/inactivation of the mgrB gene results in upregulation of the phoPQ operon and subsequent activation of the pmrHFIJKLM operon. Finally, production of L-Ara4N leads to modification of lipid A and colistin resistance.Citation51

Various mutations or disruptions of the mgrB gene have been reported, such as deletion, nonsense, missense, inactivation, and insertional mutations. According to reports, mgrB inactivation is the most common mechanism for colistin resistance in K. pneumoniae and K. oxytoca.Citation67,Citation80Citation82 In addition, it has been described that inactivation of the mgrB gene by diverse insertion sequences at different sites of this gene is the other mgrB mutation that often occurs in K. pneumoniae.Citation53,Citation65,Citation80 Other alterations that have been reported in the mgrB gene include nonsense and missense mutations, leading to premature termination and amino-acid substitutions inmgrB, respectively.Citation53,Citation77 Goulian et al showed that deletion of the mgrB gene led to upregulation of the PhoP-regulated gene in E. coli.Citation79

CrrAB two-component system

The crrAB operon encodes two proteins: CrrA as a regulatory protein and CrrB as a sensor kinase protein. Wright et al described that mutation of crrB leads to colistin resistance in K. pneumoniae.Citation83 The mutated CrrB protein regulates a crrAB-adjacent gene that encodes a glycosyltransferase-like protein, which in turn leads to modification of lipid A.Citation83 In Cheng et al's study, six amino-acid substitutions in the CrrB protein led to high resistance to colistin (MICs of colistin 512–2,048 µg/mL).Citation52 However, mutation/inactivation of the crrB gene led to activation of the pmrHFIJKLM operon and the pmrC and pmrE genes through overexpression of the pmrAB operon. Furthermore, the production and addition of L-Ara4N and PETN to lipid A lead to acquisition of resistance to colistin.Citation83 It was demonstrated that CrrC afforded a connection between the CrrAB and pmrAB systems. Mutation of the crrB gene led to increased crrC transcription. On the other hand, it has been suggested amino-acid substitutions of the CrrB protein result in increased autophosphorylation of this protein, consequently leading to colistin resistance.Citation52

Plasmid-mediated resistance to colistin

Plasmid-mediated colistin is a significant challenge and global concern, because of easy transfer of colistin-resistance genes to susceptible strains.Citation54 The mcr genes are responsible for horizontal transfer of colistin resistance. These plasmid-mediated genes were first reported in E. coli isolated from pigs and meat in China, November 2015.Citation54 MCR is a member of the PETN enzyme family, and its expression leads to addition of PETN to lipid A. According to the literature, isolates carrying the mcr1 gene display resistance to colistin without other resistance mechanisms. The existence of mcr1 in isolates is enough for colistin resistance without other resistance mechanisms, as isolates carrying this gene displayed a four- to eightfold increase in colistin MIC.Citation9 It is worth noting that the production of mcr1 leads to resistance to lysozymes.Citation84

Following initial findings, mcr1-mediating transferable colistin resistance has been reported in several regions, including Europe, Asia, the Americas, and Africa.Citation85Citation98 There is a hypothesis that mcr1 originated in animals, particularly pigs and cattle, and subsequently spread to humans, though the proportion of mcr1-positive isolates is low in humans compared to animals.Citation54,Citation99 This transmissible gene has been reported from diverse genera of Enterobacteriaceae, including E. coli, Klebsiella spp., Entrobacter spp., Salmonella spp., Shigella spp., and Cronobacter spp., but mostly from E. coli. Some plasmids containing the mcr1 gene carry other genes that are resistant to other antibiotics, such as β-lactams, aminoglycosides, quinolones, sulfonamides, tetracyclines, and fosfomycin.Citation9 The mcr gene has also been identified in Enterobacteriaceae isolates, which carry such carbapenemase genes as blaNDM1, blaNDM5, blaNDM9, blaOXA48, blaKPC2, and blaVIM1.Citation97,Citation100,Citation101

Recently, Xavier et al reported a novel plasmid-mediated colistin resistance gene, known as mcr2, in E. coli.Citation55 Thereafter, mcr3 and mcr4 genes were discovered.Citation102,Citation103 Finally, in July 2017, Borowiak et al reported a new gene of the mcr family from Salmonella paratyphi B were carried in transposons instead of plasmids.Citation104

In addition, three mobile colistin-resistance genes (mcr6, mcr7, and mcr8) were discovered in 2018. AbuOun et al discovered a new variant of mcr2 from Moraxella pluranimalium that they renamed mcr6.1.Citation105 They suggested that Moraxella spp. may contain a natural reservoir of mcr, and mcr-harboring Moraxella appeared in pig populations. Yang et al found K. pneumoniae isolates harbored a new mcr variant, mcr7.1, recovered from chickens in China.Citation106 They suggested that mcr7, like mcr-3, originated from Aeromonasspp.,Citation102 and its structure was similar to mcr3. In addition, mcr7 displayed 78% nucleotide identity to the mcr3 gene. Eventually, a new mobile genetic element, mcr-8, was discovered in K. pneumoniae. It was identified as the coexistence of mcr8 and the carbapenemase-encoding gene blaNDM, which is a great concern.Citation107 It is notable that mcr8 has existed for some time and disseminated among K. pneumoniae.Citation107 mcr28 are similar to mcr1, as PETN leads to the addition of phosphoethanolamine to lipid A, followed by colistin resistance (). Both mcr1 and mcr2 genes originated from Moraxella spp. In addition, mcr3 and mcr4 genes line up closely with PETN from Aeromonas spp. and Shewanella frigidimarina, respectively,Citation55,Citation102,Citation103,Citation108 whereas the origin of mcr5 remains unknown.Citation104 Although mcr is a plasmid-mediated gene, recently Zurfluh et al identified the mcr1 gene on chromosomes of E. coli strains. Therefore, there is a hypothesis that this gene can be integrated in the genome of some isolates.Citation109

Role of regulator RamA

The ramA locus has three genes: ramA, romA, and ramR. The ramR gene plays a role as a repressor of the ramA and romA genes. Some Enterobacteriaceae possess a ramA regulator, such as K. pneumoniae, Citrobacter spp., Enterobacter spp., and Salmonella spp. In K. pneumoniae, this regulator modulates lipid A biosynthesis and is related to permeability barriers. It has been shown that ramA alterations lead to reductions in colistin susceptibility. Recently, researchers showed that increased levels of RamA resulted in LPS modification and increased resistance to colistin.Citation110 RamA applied changes tothe bacterial surface and Klebsiella survived against colistin. Several genes are associated with lipid A biosynthesis, including lpxA, lpxC, lpxD, lpxB, lpxK, lpxL, lpxM, and lpxO.Citation111 RamA binds directly to and activates the lpxC, lpxO, and lpxL2 genes and leads to alterations within the lipid A moiety in K. pneumoniae. Therefore, Klebsiella can survive in such antibiotic challenges as colistin.Citation110

Role of capsule in colistin resistance

The role of capsular polysaccharide (CPS) has been demonstrated to be protective against cationic antimicrobial peptides, including colistin.Citation35 K. pneumoniae is able to release CPS from its surface.Citation112 The number of capsule layers is related to resistance level. It has been observed that K. pneumoniae with several layers was more resistant to colistin than isolates with few layers.Citation8,Citation113 However, upregulation of a capsular biosynthesis gene led to a reduction in the interaction of colistin with the target site in K. pneumoniae, followed by increased colistin resistance.Citation35 Consequently, there are some regulators of capsule formation, such as Cpx (conjugative pilus expression) and Rcs (regulator of capsule synthesis). Cpx and Rcs also appear to contribute to colistin resistance by activating the efflux pump KpnEF and regulating the PhoPQ TCS, respectively.Citation46 Furthermore, the ugd gene plays a role in CPS and L-Ara4N biosynthesis in that its phosphorylation is related to the synthesis of capsular and colistin resistance.Citation114,Citation115

Role of efflux pumps

A few studies have suggested that efflux-pump systems are involved in colistin resistance. Efflux pumps, such as the KpnEF, AcrAB and Sap proteins, have been reported in Enterobactericeae. By activation of these pumps, resistance to colistin is increased.Citation116,Citation117 The efflux pump KpnEF is a member of the Cpx regulon (responsible for capsule synthesis in K. pneumoniae) and belongs to the SMR protein family.Citation8 In K. pneumoniae, this pump is mediated by colistin resistance and other antibiotics, including ceftriaxone, erythromycin, and rifampicin.Citation117 It has been observed that mutations in KpnEF (as a member of the small MDR efflux-pump family) lead to more susceptibility and a doubled reduction inthe MIC of colistin.Citation117 On the other hand, AcrAB is a part of the AcrAB–TolC complex, which plays a role in colistin resistance. The AcrAB-mutant E. coli displays aneightfold increase in colistin susceptibility. It has been remarked that expression of this pump's proteins is dependent on the PhoPQ TCS.Citation118 Finally, the SapABCDF operon encodes Sap proteins that are constitute of five proteins.Citation118 In the mutant of P. mirabilis, susceptibility to colistin is increased by mutation of the SapABCDEF operon.Citation42 It has been shown that the use of efflux-pump inhibitors in the test medium carbonyl cyanide 3-chlorophenylhydrazone leads to a reduction in MIC for colistin-resistant strains.Citation119

Logical approaches to use of colistin

Recent studies have suggested colistin is the foremost therapeutic option of XDR Gram-negative bacteria in recent years, owing to its potent bactericidal efficacy.Citation120 Combination therapies of colistin with other antibiotics are superior to colistin monotherapy for XDR strains, due to rapid selection of resistance in some strains, heteroresistance during colistin monotherapy, and lower clinical efficacy during colistin-based combination.Citation121 In addition, rates of cure, 14-day survival, and microbiological eradication are lower in monotherapy compared to combination therapy.Citation121 Moreover, several combination therapies have been recommended to decrease the development of resistance. The combination of colistin with other drugs, such as carbapenems, sulbactam, tigecycline, aminoglycosides, and rifampicin, has been recommended to prevent the development of colistin-resistant strains, which may improve clinical and microbiological outcomes.Citation121Citation126 The colistin–sulbactam combination was recommended against imipenem-resistant A. baumannii, particularly in colistin-resistant strains, due to its high in vitro synergistic activity,Citation121,Citation127 which may be a more favorable combination. Colistin-based combinations with tigecycline, aminoglycosides, and rifampicin have shown synergistic activity against XDR strains,Citation122,Citation125,Citation128 but tigesycline is disadvantageous in bacteremic patients, because of its low plasma concentrations.Citation128 In addition, colistin–carbapenem combinations may be preferable in the treatment of A. baumannii infections to prevent resistance selection and to decrease the prevalence of A. baumannii.Citation121

Conclusion

The main target for colistin is lipid A of the LPS in Gram-negative bacteria, leading to disruption of the bacterial membrane and resulting in cellular death. In recent decades, the increasing use of colistin in clinical settings, mainly in veterinary clinics, has led to the emergence of colistin resistance. Many studies have shown that the prevalence of colistin resistance has increased rapidly among Enterobacteriaceae. Clinicians should be alert to the possibility of colistin resistance among MDR bacteria and the development of colistin resistance through mutation or adaptation mechanisms. Rapidly emerging bacterial resistance has made it harder for us to rely completelyon the discovery of new antibiotics; therefore, we need to have logical approaches to use older antibiotics, such as colistin.

Acknowledgments

This study received no funding, and was the authors' own work. We thank the staff of the Drug Applied Research Center for their support.

Disclosure

The authors report no conflicts of interest in this work.

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