Letters in Applied Microbiology, 2023, 76, 1–13

https://doi.org/10.1093/lambio/ovad023
Advance access publication date: 8 February 2023
Review Article

Colistin resistance mechanisms in Gram-negative bacteria:

a Focus on Escherichia coli
Mohammad Abavisani 1 , Narjess Bostanghadiri2 , Hossein Ghahramanpour3 , Mansoor Kodori4,* ,
Fariba Akrami5 , Hadis Fathizadeh6,7 , Ali Hashemi8 , Mohsen Rastegari-Pouyani9
1
Student Research Committee, Mashhad University of Medical Sciences, 9138813944 Mashhad, Iran
2
Department of Microbiology, School of Medicine, Iran University of Medical Sciences, 1449614535 Tehran, Iran

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3
Department of Bacteriology, Faculty of medical sciences, Tarbiat Modares University, 1411713116 Tehran, Iran
4
Noncommunicable Diseases Research Center, Bam University of Medical Sciences, 7661771967 Bam, Iran
5
INRS-Centre Armand-Frappier Sante Biotechnologie, H7V 1B7 Laval, Quebec, Canada
6
Student Research Committee, Sirjan School of Medical Sciences, 7816916338 Sirjan, Iran
7
Department of Laboratory sciences, Sirjan School of Medical Sciences, 7816916338 Sirjan, Iran
8
Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, 1985717443 Tehran, Iran
9
Department of Immunology, School of Medicine, Hamadan University of Medical Sciences, 6517838678 Hamadan, Iran
∗
Corresponding author. Noncommunicable Diseases 9Research Center, Bam University of Medical Sciences, Bam, Iran. E-mail: [email protected];
Iran, Bam, Shahid Rajaie Blvd., Bam university Of Medical Sciences and Health Services.

Abstract
Multidrug-resistant (MDR) Escherichia coli strains have rapidly increased worldwide, and effective antibiotic therapeutic options are becoming
more restricted. As a polymyxin antibiotic, colistin has a long history of usage, and it is used as a final line of treatment for severe infections
by Gram-negative bacteria (GNB) with high-level resistance. However, its application has been challenged by the emergence of E. coli colistin
resistance. Hence, determining the mechanism that confers colistin resistance is crucial for monitoring and controlling the dissemination of
colistin-resistant E. coli strains. This comprehensive review summarizes colistin resistance mechanisms in E. coli strains and concentrates
on the history, mode of action, and therapeutic implications of colistin. We have mainly focused on the fundamental mechanisms of colistin
resistance that are mediated by chromosomal or plasmid elements and discussed major mutations in the two-component systems (TCSs) genes
and plasmids that transmit the mobilized colistin resistance resistant genes in E. coli strains.

Significance and impact of the study:

Colistin has attracted considerable interest globally due to the increasing prevalence of multidrug-resistant (MDR) and carbapenem resistance
Gram-negative bacteria (GNB). Unfortunately, increased use of colistin in clinical settings, often associated with the treatment of severe infections
as a last-line option, has resulted in resistance in bacterial pathogens such as Escherichia coli. Moreover, the rapid global spread of mobilized
colistin resistance (mcr) genes from animal reservoirs to humans poses a severe danger to the clinical use of colistin. Infections characterized by
colistin resistance have been documented to have different results, with some evidence representing a substantial risk of in-hospital mortality.
The elucidation of colistin resistance mechanism is fundamental for tracking the spread of these emerging isolates. This review will provide
essential information on all aspects of colistin, emphasizing the mechanism of colistin resistance in E. coli and illustrating the overall status of
resistance in clinical isolates of E. coli.
Keywords: Escherichia coli, colistin, antibiotics resistance, mcr-genes, Gram-negative bacteria

Introduction (PAIs) and recombining foreign DNA into host DNA (Javadi
Escherichia coli is the most common opportunistic bacterial et al. 2017). Escherichia coli can operate as a donor and re-
pathogen in humans and animals. It causes various hospital- cipient of resistance genes and a conduit for resistance gene
acquired and community-acquired diseases, especially gas- exchange to other bacteria (Poirel et al. 2018). On the other
troenteritis, urinary tract infections (UTIs), and bloodstream hand, treatment of E. coli infections is jeopardized by the ad-
infections (Wang et al. 2016). Regardless of their susceptibility vent of highly resistant strains, resulting in prolonged hospi-
to the most widely administered therapeutic antibiotics, E. coli talization, raised costs, and a push toward using the latest gen-
bacteria potentially acquire resistance genes via interspecies eration of antibiotics that retain maximal efficacy (Tacconelli
and intraspecies horizontal gene transfer (HGT) (Poirel et al. et al. 2018). Because of the significant rise in infections caused
2018). by multidrug-resistant (MDR) E. coli, colistin (Polymyxin E)
Antimicrobial resistance is a global concern and is driven is widely utilized in the clinic (Klein et al. 2018). However, col-
by the intensive consumption and improper use of antimi- istin resistance in E. coli has been increasingly reported, and
crobial agents for treatment of infection and prophylaxis of the clinical use of colistin has been challenged by the rapid dis-
some infections in farm animals. The HGT mechanisms in- semination of plasmid-borne colistin resistance, following the
clude transferring mobile genetic elements such as plasmids, initial identification of mcr-1 plasmids in animals and human
transposons, insertion elements, phages, pathogenicity islands clinical settings in China in 2015 (Liu et al. 2016b)). Fur-

Received: April 19, 2023. Revised: November 28, 2022. Accepted: February 7, 2023

C The Author(s) 2023. Published by Oxford University Press on behalf of Applied Microbiology International. All rights reserved. For permissions, please

e-mail: [email protected]
2 Abavisani et al.

Table 1. Antibiotics resistance mechanism in E. coli.

Antibiotic Mechanism Resistance determinant Reference

β-Lactam β-lactamase production, TEM, SHV, CMY, CTX-M (Nikolićet al. 2018)
alteration of porin channels,
AmpC-type
cephalosporinases,
overproduction of specific
β-lactamases, and
inhibitor-resistant
mutations.
Carbapenem Carbapenemase enzymes KPC, NDM, VIM, (Hanet al. 2020)
production, mutations in OXA-48, IMP
efflux pumps
Fluoroquinolone Chromosomal target site gyrA, parC. (Hopkinset al. 2005;

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mutations Bhatnagar and Wong 2019;
Malekzadeganet al. 2019)
Plasmid-borne resistance qnrA,B,C,D, S aac (6’)-Ib-cr
mechanisms oqxAB, qepA
Phenicol Inactivation of Cat (Schwarzet al. 2004)
nonfluorinated phenicols by
chloramphenicol
acetyltransferases.
Active efflux of cmlA
nonfluorinated phenicols floR
Nonfluorinated phenicols
Methylation by an rRNA Cfr
methylase
Tetracycline Efflux pumps tet A, tet B, tet C, tet D, tet (Poirelet al. 2018)
E, tet G, tet J, tet L, tet Y
Ribosome protective tet M, tet W
proteins genes
Oxidoreductase inactivates tet X
gene
Sulfonamides _ sul1, sul2, sul3 (Zhouet al. 2021)
Trimethoprim _ dfrA, dfrB (Liet al. 2020)

thermore, multiple investigations have reported various mcr- hibitor combinations, fluoroquinolones, aminoglycosides,
positive E. coli (MCRPEC) isolates from humans and animals and trimethoprim-sulfamethoxazole (Bartoletti et al. 2016).
belonging to different sequence types (STs), globally. To date, Unfortunately, the widespread use and abuse of antibiotics
ten mcr genes (mcr-1 to mcr-10) have been detected in animals from different classes has resulted in increased rates of an-
and humans, and mcr genes have also been identified in more tibiotic resistance in health care settings and communities.
than 50 countries (Zhang et al. 2021). Recent reports indicate Recent surveillance data demonstrate that resistant E. coli
that four of 1028 E. coli strains recovered from patients were strains have appeared as a global threat, with high levels
carbapenem- and colistin-resistant. In addition, these strains of antibiotic resistance to multiple classes of antibiotics
had an MDR phenotype, exhibited resistance to quinolones (Xiao et al. 2019, Zhang et al. 2021). The phenomenon
and cephalosporins, and were obtained from elderly patients. of resistance has emerged by the virtue of development of
They also declared that carbapenem and colistin resistance many different mechanisms such as mutation in target sites,
is mainly related to the presence of blaNDM-1, blaTEM-1, antibiotic inactivation and production of modifying enzymes
and mcr-1 genes (Na et al. 2021). The increasing clinical ap- such as β-lactamase and carbapenemases. Resistance can
plication of colistin has drawn attention to the mechanisms transmitted toward other strains via releasing the antibiotic
of acquired colistin resistance in numerous MDR opportunis- resistance genes on vectors, including transmissible plasmids,
tic pathogens such as E. coli (Janssen and van Schaik 2021). integrons, and transposons. Besides, porin mutations, and
MDR carbapenem-resistant Enterobacteriaceae (CRE) infec- modified permeability to antibacterial compounds due to
tions are becoming more common, which means that rela- potential of efflux pumps are other mechanisms of resistance
tively toxic drugs like colistin are being used more often to (Table 1) (Pitout 2012, Abavisani et al. 2021). Resistance
treat these infections (Biswas et al. 2012). Colistin is increas- to β-lactam antibiotics is mediated by the production of
ingly being utilized as a last option to treat challenging and β-lactamase [most notably plasmid-bound cephalosporinases
complicated infections caused by MDR E. coli strains (Heuer and extended-spectrum-beta-lactamases (ESBLs)], alteration
et al. 2010). Hence, this review aims at comprehensively re- of porin channels, AmpC-type cephalosporinases, over-
viewing the genetic mechanisms of colistin resistance in E. coli. production of specific β-lactamases and inhibitor-resistant
mutations. TEM and SHV-lactamase are two recently found
and well-known ESBLs in E. coli strains (Eslami et al. 2016).
Antibiotics resistance in E. Coli ESBLs can hydrolyze penicillins, first-, second- and third-
Most E. coli infections are treated with penicillins, generation cephalosporins, aztreonam, cefamandole, and
cephalosporins, monobactams, β-lactam/β-lactamase in- cefoperazone and are inhibited by β-lactamase inhibitors,
Colistin resistance in the Escherichia coli 3

including piperacillin/tazobactam, ampicillin/sulbactam, Despite recent innovations, there is still a lack of appro-
and amoxicillin/clavulanic acid (Bush and Bradford 2016). priate alternatives for treating MDR and XDR GNB strains,
Piperacillin/tazobactam is mainly recommended for the em- with colistin remaining the medicine of last resort (Karaiskos
pirical treatment of severe infections; however, this antibiotic et al. 2013). Previous studies have suggested that disruption of
might not be so effective in regions with a high prevalence of the outer membrane (OM) in GNB is the primary mechanism
ESBL-positive E. coli strains (Rodríguez-Villodres et al. 2021). of action for polymyxin antibiotics like colistin (Le Guern et
Unlike ESBL, AmpC β-lactamase is resistant to cephamycins al. 2017). Colistin having cationic aminobutyric acid (Dab)
and is not inhibited by β-lactamase inhibitors (Marsik and residues can interact with anionic phosphate groups on the
Nambiar 2011, Harris and Ferguson 2012). Carbapenems lipid A of the lipopolysaccharide (LPS) moiety in OM, result-
have conventionally been used for treating patients with ing in the competitive displacement of Ca2+ and Mg2+ di-
severe infections caused by AmpC- and ESBL-positive strains. valent cations that weaken OM stability. Subsequently, bac-
Escherichia coli strains resistant to these agents have been terium death is followed by loss of integrity of OM and
regarded as a global threat to public health with irreparable the leakage of periplasmic and cytoplasmic contents through
consequences (van Duin and Doi 2017). In 2017, the WHO permeabilization via localization in the OM (Dupuy et al.

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listed CRE as a priority for discovering new antibiotics (Gai 2018). Additionally, colistin has a lower affinity for mam-
et al. 2019). I this regard, the genes encoding carbapenemases, malian cell membranes, as, unlike bacterial membranes, they
the most common of which being NDM and OXA-48 genes, have a neutral charge at physiological pH (Gai et al. 2019).
are one of the resistance-promoting mechanisms (Goodman et Other mechanisms of action for colistin bactericidal proper-
al. 2016, Han et al. 2020). Fluoroquinolones are also consid- ties have been hypothesized in addition to detergent-like ac-
ered critical antimicrobial agents for the treatment of various tivities. It has been proposed that the OM can fuse with the
infections. Resistance to fluoroquinolones occurs by different cytoplasmic membrane through a vesicle–vesicle contact path-
mechanisms, including chromosomal mutation in gyrA and way, in which colistin binds to anionic phospholipid vesicles
parC genes and plasmid-encoded resistance genes such as after transitioning over the OM. The loss of phospholipids,
Qnr-like proteins, the AAC (6)-Ib-cr acetyltransferase, and osmotic imbalance, and cell death may arise from phospho-
active QepA and OqxAB efflux pumps (Redgrave et al. 2014, lipid exchange between the two membranes (El-Sayed Ahmed
Rodríguez-Martínez et al. 2016). In a study by Shuzhen Xiao et al. 2020). Colistin killing may also result from production
et al., among the strains isolated from bloodstream infections, of reactive oxygen species (ROS) in the hydroxyl radical death
the highest resistance rates were reported for penicillins, first- pathway. Inhibition of NADH oxidase enzymes necessary for
and second-generation cephalosporins, and fluoroquinolones bacteria survival has been reported for some GNB organisms
(Xiao et al. 2022). Third-generation cephalosporins are like E. coli (Deris et al. 2014).
often recommended to treat such infections, though their
excessive consumption has led to increased resistance rates
(MacKinnon et al. 2021, Clemenceau et al. 2022, Milano Significance in the antibiotic resistance era
et al. 2022). Significantly increased prevalence of β-lactam, Antibiotic resistance has been rising and spreading for more
fluoroquinolone and carbapenem resistance, and the lack of than half a century. It is currently one of the twenty-first cen-
effective therapeutic agents against these resistant strains, has tury’s most urgent public health challenges worldwide, par-
led to the introduction of colistin as the last alternative for ticularly among GNB species. WHO estimates that if exist-
eradicating these infections (Biswas et al. 2012, Kassem et al. ing trends continue, 10 million people will die each year by
2019). 2025 (Wang et al. 2020a). MDR, XDR, and even pan drug-
resistant (PDR) bacteria pose the greatest threat, as they are
resistant to all clinically available drugs. For many years, Car-
bapenem antibiotics have been considered the most effective
Colistin broad-spectrum β-lactam against MDR GNB (Awan et al.
History and mechanism of action 2021, Charles et al. 2022). However, numerous studies have
Colistin, also known as polymyxin E, is an amphipathic, non- increasingly reported the diverse cases of carbapenem resis-
ribosomally synthesized, cyclic lipopeptide antibiotic utilized tance through various mechanisms. Consequently, colistin and
to treat GNB infections. In 1947, Coyama and colleagues in tigecycline are two antibiotics presented as the last therapeutic
Japan purified colistin and other polymyxins from the soil- alternatives for infections rendered by carbapenem-resistant
dwelling bacterium Bacillus polymyxa subspecies (subsp) col- organisms (Khoshbayan et al. 2022). Colistin has been in-
istinus (Wilkinson and Lowe 1964). Colistin was later licensed cluded as a part of livestock feed for decades to improve
by the US Food and Drug Administration (FDA) in 1959 to growth and control intestinal infections (Kumar et al. 2020).
treat various infections, including UTIs, diarrhea, and bowel There seem to be currently no restrictions on the use of colistin
decontamination. Colistin was extensively employed due to its in some Central America and Asia countries, but it has been
promising and rapid bactericidal activity. Because of its side banned in a number of countries, including Argentina, Brazil,
effects, including nephrotoxicity and neurotoxicity, as well as Peru, Bolivia, Paraguay, Mexico, India, Japan, Malaysia, and
the discovery of two novel antibiotics, carbenicillin and gen- Thailand. However, the European Union prohibits its use in
tamicin, colistin clinical application was mainly substituted animal feed, and its usage has never been allowed in the United
with safer antimicrobial agents (Koch-Weser et al. 1970, Spa- States and Canada (Olaitan et al. 2021). Colistin is an effi-
pen et al. 2011). A two-decade hiatus with considerably in- cient treatment for diarrhea caused by E. coli, which is un-
creased β-lactam and carbapenem-resistant bacteria in the common in poultry but is utilized as a growth promoter (Ku-
mid1990s resulted in the reintroduction of colistin as a key mar et al. 2020). According to reports from India, approxi-
therapeutic option against these organisms (Aslan and Akova mately 57% of GNBs are carbapenem-resistant, and colistin
2022). is essential for treating acute infections caused by GNBs in
4 Abavisani et al.

humans (Davies and Walsh 2018). Fortunately, colistin pro- ably acts more efficiently in combination (Biswas et al. 2012).
duction has decreased recently, and its use has been outlawed Many in vitro experiments have revealed synergism between
in several countries. However, the poultry and swine industries two antibiotics in the laboratory; however, predictions from
utilize 96% of colistin globally (Wang et al. 2020b). Another in vitro studies may not translate to clinical trial outcomes
study found that E. coli isolates from animals tended to be (Liu et al. 2016a, Soudeiha et al. 2017, Nutman et al. 2020).
resistant to colistin via the mcr-dependent mechanisms and In 2018, Abdelsalamand et al., demonstrated the advantage
also declared that older and adult animals may be a reservoir of colistin–meropenem combination over colistin monother-
of E. coli resistant strains. These reports imply that the an- apy in 60 pneumonia patients infected by MDR K. pneumo-
imal’s usage of colistin may be contributed to the evolution niae strains. The combined therapy group had a 2.6-fold re-
of bacterial acquired resistance toward colistin (Zhang et al. duced mortality rate compared to the monotherapy group. In-
2019). terestingly, the incidence of nephrotoxicity did not change sig-
nificantly between the two groups (Abdelsalam et al. 2018).
In another trial conducted on 406 patients who suffering
Colistin side effects and meropenem combo from severe infections caused by the carbapenem-resistant

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therapy GNB, colistin-meropenem combination compared with col-
Currently, colistin is most widely used to treat life-threatening istin monotherapy showed no significant difference in clini-
infections caused by Klebsiella pneumoniae, Pseudomonas cal failure (73% and 79%) at day 14. Furthermore, the inci-
aeruginosa, Acinetobacte baumannii, E. coli, and other En- dence of diarrhea increased (27% versus 16%), and the mor-
terobacteriaceae (Aghapour et al. 2019). Although the fre- tality rate was equal. Nevertheless, a slight reduction in the
quency of colistin resistance is not prevalent, adverse effects incidence of mild renal failure was observed in the at-risk pa-
like nephrotoxicity, hepatotoxicity, and neurotoxicity have re- tients. As a result, this study does not support the superiority
stricted colistin medical usage (Wagenlehner et al. 2021). Neu- of colistin-meropenem combination therapy, unlike the previ-
rotoxicity occurrence is rare and mild, and the patient will re- ous study (Paul et al. 2018).
cover shortly after treatment stoppage (Lim et al. 2010). The There have been reports of E. coli strains that are resistant
most commonly reported adverse consequence is nephrotoxic- to carbapenem antibiotics, restricting treatment options to an-
ity. Colistin causes renal damage via increasing tubular epithe- tibiotics such as colistin (Sidjabat and Paterson 2015). Based
lial cell membrane permeability, followed by influx of cations, on recent data, the prevalence of carbapenem resistance in
anions, and water molecules into cells leading to swelling, and E. coli varied for different regions: North India 15.6%, East
cell lysis (Ordooei Javan et al. 2015). It has been demonstrated Africa 12%, Iran 5% Europe 0%–7%, and North America
that nephrotoxicity prevalence was 26.7% and 29.8% for col- 0.2%–0.4% (Ssekatawa et al. 2018, Jaggi et al. 2019, Nord-
istin and polymyxin B in adult patients, respectively (Oliota mann and Poirel 2019, Nasiri et al. 2020). Unfortunately, the
et al. 2019). In addition to the colistin dose, internal and reports of resistance E. coli strains are rising in the medicine
external variables can strongly influence colistin-associated and food industries (Dawadi et al. 2021).
nephrotoxicity, including concurrent administration of other
nephrotoxic drugs, diuretics, vasopressors, and nonsteroidal
anti-inflammatory drugs, or other antibiotic classes. Colistin Colistin resistance mechanisms in GNB
side effects are also influenced by patients’ characteristics such Colistin resistance mainly occurs due to the modification of
as age, sex, hyperbilirubinemia, hypoalbuminemia, the under- lipid A moiety of LPS, similar to that observed in bacteria with
lying disease, and the severity of disease (Lameire et al. 2021, intrinsic resistance to polymyxins (Yang et al. 2017, Kim et al.
Pickkers et al. 2021). 2019b). These modifications decrease the LPS/membrane neg-
In 2022, Sangthawan and colleagues examined the charac- ative net charge by shielding phosphate and carboxyl groups
teristics and risk factors associated with colistin nephrotoxic- to hinder colistin binding and action. Other mechanisms like
ity in 381 patients treated with colistin in Thailand from 2015 efflux pumps, loss of lipid A, OM remodeling events, and cap-
to 2019. sule formation have been suggested in Enterobacteriaceae (De-
Compared to earlier studies, the rate of colistin-associated lannoy et al. 2017, Kim et al. 2019b, Ayoub Moubareck 2020,
nephrotoxicity (74%) was relatively high. The prevalence of Binsker et al. 2021).
nephrotoxicity after colistin treatment ranged widely from LPS modification usually involves replacing the phos-
25% to 76%, as previously described (Hassan et al. 2018). phate groups of lipid A with 4’-phosphoethanolamine (PEtN)
Along with higher hospital admission costs, patients with and/or cationic 4-amino-4-deoxy-L-arabinose (L-Ara4N) (El-
nephrotoxicity had a 2-fold increased mortality rates than Sayed Ahmed et al. 2020). The L-Ara4N modification is more
non-nephrotoxic patients. The main risk variables were age effective than PEtN because of the resultant less negative
>60 years, comorbidities, serum albumin < 3.5 g/dL, and con- charge (−1.5 to −1 for PEtN versus 0 for L-Ara4N) (Olai-
comitant nephrotoxic medications (Sangthawan et al. 2021). tan et al. 2014).
Another study found that 50.6% of patients infected with L-Ara4N-mediated modification rate is relatively much
XDR A. baumannii who received colistin developed acute kid- higher than PEtN-mediated modification (Olaitan et al. 2014).
ney damage, and 10.2% had a severe disease. Although ad- Resistance to colistin can be chromosomally mediated or
vanced age and the prevalence of chronic kidney diseases like plasmid-mediated (Poirel et al. 2018). Regardless of the mech-
renal dysfunction were similar in patients, there was no corre- anism of LPS modification, a recent study showed that al-
lation between mortality rate and colistin-associated nephro- though modified LPS is present on both outer and cytoplasmic
toxicity (Durante-Mangoni et al. 2016). An established strat- membranes of E. coli, it protects the permeability of the cyto-
egy to lessen colistin toxicity while maintaining antibiotic ef- plasmic membrane but not the OM from damage (Humphrey
ficacy is the combination therapy of colistin with other an- et al. 2021). It may be due to the fact that not all LPS molecules
tibiotics like meropenem that has less toxicity and presum- are altered in either membrane, and colistin can interact with
Colistin resistance in the Escherichia coli 5

The pmrCAB operon encodes three proteins: (1) the

phosphoethanolamine phosphotransferase PmrC (also called
EptA) that adds a pEtN group to the LPS, (2) the transcrip-
tional regulator PmrA (also known as BasR), and (3) the sen-
sor kinase protein PmrB (also called BasS). PmrAB usually gets
activated by environmental changes like the presence of an-
timicrobial peptides (polymyxins), Fe3+ , Mg2+ level and low
pH. PmrB activates PmrA by phosphorylation, and PmrA acti-
vates the transcription of the pmrCAB operon, the arnBCAD
operon (also known as pmrHFIJKLM or pbgPE operon),
and the pmrE gene involved in LPS modification (Kim et al.
2019b). The ArnBCADTEF operon and pmrE encode the pro-
teins involved in the biosynthesis of L-Ara4N and its transfer
(Kim et al. 2019).

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The PhoPQ is naturally activated by low environmental pH
and Mg2+ and phagosomes, and this TCS encodes the regula-
tor protein PhoP and the sensor protein kinase PhoQ. PhoQ
responds by activating PhoP through phosphorylation, lead-
ing, in turn, to the expression of genes coding for magne-
sium transportation, the arnBCADTEF, and pmrD (Poirel et
al. 2017). PhoP and PmrA are directly or indirectly associated
via PmrD. Thus, when PmrD is activated, it upregulates Pm-
rAB and binds to PmrA to stabilize its phosphorylated state
(Kim et al. 2019b, El-Sayed Ahmed et al. 2020). (Kim et al.
2019; El-Sayed Ahmed et al. 2020). PhoP also upregulates
the mgrB gene, which encodes a protein that downregulates
PhoQ. Hence, overexpression of the PhoPQ system, pmrHFI-
JKLM operon activation, and the production of L-Ara4N re-
sponsible for colistin resistance can be mediated by inactiva-
tion of MgrB (Fig. 1) (Poirel et al. 2017).

Chromosome-mediated resistance to colistin in E.

Figure 1. Chromosomal- and plasmid-mediated colistin resistance in E. Coli
coli. PmrB, a transmembrane sensor protein kinase, normally is activated Each genus of Enterobacteriaceae has its characteristic muta-
by environmental low pH, high Fe+ and Al3+ ions. Activated PmrB, tion type and associated genes related to colistin resistance.
phosphorylates PmrA, which the upregulates pmrCAB and arnBCADTEF In E. coli, mutations in the sensor kinases happen more fre-
operons that modify lipid A by adding PEtN and L-Ara4N, respectively.
Lipid A modification leads to a less negative charge of the OM, thus
quently than in TCS response regulators (Kim et al. 2019b).
inhibiting colistin entrance. Low pH and Mg2+ ions active PhoQ, another Many distinct mutation profiles in several regions of TCS have
sensor protein kinase that activates PhoP by phosphorylation. Activating been identified in E. coli strains isolated from different coun-
PhoP leads to the expression of several genes, including PmrD and tries and from human or animal (pigs, chicken, etc.) specimens
arnBCADTEF operan. PmrD connects PhoPQ and PmrAB by stabilizing (Binsker et al. 2021) (Table 2).
phosphorylated PmrA. PhoP also regulates mgrB expression, and MgrB Concerning PmrA, two hotspots for missense mutations af-
inhibits PhoQ activity. Overexpression of different parts of TCSs and their
fecting the AAs G53 and R81 have been identified, and the
regulators leads to chromosomally mediated resistance to colistin, or
colistin resistance in E. coli is also mediated by plasmid-borne colistin G53A mutation in human clinical blood isolate has been con-
resistance genes (mcr). Mcr genes encode Mcr, which is a firmed experimentally to mediate colistin resistance (Bourrel
phosphoethanolamine transferase enzyme that modifies lipid A by adding et al. 2019, Janssen et al. 2020b) (Table 2). PmrB seems to
PEtN, resulting in a less negative net charge of the membrane, similar to be the more common target site for mutations compared to
the chromosomal pathways. PmrA (Binsker et al. 2021). Hotspots for mutations were AAs
L14, P94, E121, T156, V161, with effects on the HAMP and
the HisKA domain of the protein (Binsker et al. 2021). Iden-
unmodified LPS molecules in OM. In addition, it has been re- tified colistin-resistant mutations included L10R in a blood
ported that the CM of the MCR-1 strain contains consider- isolate, L10P in a human urinary tract isolate, substitution
able levels of modified LPS. As a result, the CM of E. coli is of G19E from a rectal swab isolate, and deletion of 27–
shielded against colistin by the MCR-1 pEtN transferase but 45 (LISVFWLWHESTEQIQLFE), G206D from human clin-
not the OM, since the CM contains only a limited number of ical specimens and addition of an extra HAMP domain from
unmodified LPS molecules that colistin can target (Humphrey a human blood isolate (Cannatelli et al. 2017, Delannoy et al.
et al. 2021). 2017, Sato et al. 2018, Bourrel et al. 2019, Kim et al. 2019b,
Different molecular components are accountable for chro- Janssen et al. 2020a, Janssen et al. 2020b). In the case of PmrC
mosomal resistance in GNB. In Enterobacteriaceae, alter- transferase, AA alteration, including T148A and K233T, were
ations in related two-component systems (TCS), PhoPQ, and found in the transferase domain of the protein, although these
PmrAB, and their regulatory gene, i.e. the mgrB gene, are re- were not experimentally confirmed to confer colistin resis-
sponsible for resistance (Fig. 1). tance (Choi et al. 2020).
6 Abavisani et al.

Table 2. Chromosomal mutations associated with colistin resistance in E. coli.

Amino acid (AA) Experimentally

Gene ST 1 /Source Protein domain change confirmed mutation Country Reference

PmrA Ns 2 /Human REC 3 (1–112) G15R - France (Bourrelet al. 2019)

Ns/Chicken REC (1–112) S29G - Canada, (Vounbaet al. 2019)
Senegal and
Vietnam
Ns/Swine REC (1–112) S39I - Spain (Quesadaet al. 2015)
131/ Human REC (1–112) G53A Confirmed Netherlands (Janssenet al. 2020b)
Ns/ Human REC (1–112) G53A or G53C or - France (Bourrelet al. 2019)
G53E or G53R or
G53S or G53V or
G53W
Ns/ Avian REC (1–112) A80V - United States (Kathayatet al. 2020)

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Ns/ Human REC (1–112) R81L or R81S - France (Bourrelet al. 2019)
131/ Human REC (1–112) L105P Confirmed Japan (Satoet al. 2018)
Ns/ Pig - G144S - France (Delannoyet al. 2017)
PmrB 648/ Human - 6-11 RPISLR Confirmed Netherlands (Janssenet al. 2020b)
Ns/ Human - 7–12 - Switzerland (Poirelet al. 2017)
59/ Human - L10P Confirmed Italy (Cannatelliet al. 2017)
131/ Human - L10R Confirmed Netherlands (Janssenet al. 2020b)
Ns/ Avian - L14Q - United States (Bourrelet al. 2019)
38/ Human TM1 (15–34) G19E Confirmed Netherlands (Janssenet al. 2020b)
131/ Human TM1 (15–34) 27-45 LISVFWL- Confirmed Japan (Satoet al. 2018)
WHESTEQIQLFE
Ns/ Human TM2 5 (66-88) C84R or C84Y - France (Bourrelet al. 2019)
Ns/ Avian HAMP (89–141) T92P - United States (Kathayatet al. 2020)
Ns/ Pig HAMP R93P - China (Kuanget al. 2020)
(89–141)
Ns/ Human HAMP P94A or P94L or - France (Bourrelet al. 2019)
(89–141) P94Q or P94S
10/ Human HAMP A118T - China (Luoet al. 2017)
(89–141)
Ns/ Human HAMP E121K or E121Q - France (Bourrelet al. 2019)
(89–141)
14/131 Human HAMP E123D - China (Luoet al. 2017)
(89–141)
Ns/ Pig HAMP E123D - France (Delannoyet al. 2017)
(89–141)
Ns/ Human HisKA T147A - France (Bourrelet al. 2019)
(142–202)
Ns/ Pig HisKA T156A - France (Delannoyet al. 2017)
(142–202)
Ns/ Human HisKA T156K - Switzerland (Poirelet al. 2017)
(142–202)
Ns/ Human HisKA T156M - France (Bourrelet al. 2019)
(142–202)
Ns/ Human HisKA A159P - France (Bourrelet al. 2019)
(142–202)
Ns/ Human HisKA A159V - Switzerland (Poirelet al. 2017)
(142–202)
Ns/ Pig HisKA G160E - France (Delannoyet al. 2017)
(142–202)
Ns/ Swine HisKA V161G - Spain (Quesadaet al. 2015)
(142–202)
Ns/ Human HisKA E166K - France (Bourrelet al. 2019)
(142–202)
416/131/ Human - G206D Confirmed Japan (Satoet al. 2018)
641/ Calf HATPase c D283G - Japan (Rebeloet al. 2018)
(249–357)
Ns/ Pig HATPase c D283G - France (Delannoyet al. 2017)
(249–357)
38/ Human HATPase c Y315F - China (Luoet al. 2017)
(249–357)
Ns/Pig HATPase c V351I - France (Delannoyet al. 2017)
(249–357)
101/140/ Human - Y358N - China (Luoet al. 2017)
131/ Human TM1 (13–35) Extra HAMP Confirmed Netherlands (Janssenet al. 2020b)
domain
PmrC 1/ Isolate from Transferase domain T148A, K233T - South Korea (Choiet al. 2020)
animal and plant
quarantine agency
Colistin resistance in the Escherichia coli 7

Table 2. Continued

Amino acid (AA) Experimentally

Gene ST 1 /Source Protein domain change confirmed mutation Country Reference

PhoP Ns/ Pig REC (1-112) V108M - France (Delannoyet al. 2017)
PhoQ 354/ Human - N346K - Italy (Cannatelliet al. 2017)
3997/ Human HATPase c E375K - Switzerland (Nordmannet al. 2016)
(374–480)
PmrD Ns/ Animal - N11D - South Korea (Kim et al. 2019b)
sample
Ns/ Animal - M20
sample
Ns/ Animal - A27T
sample
Ns/ Animal - K35N

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sample
Ns/ Animal - A52V
sample
3054, 224, 6488, - K82T
2035, 278, 448,
906, 4038, 156/
Animal sample
MgrB Ns/ Pig V8A - France (Delannoyet al. 2017)
Ns/ Pig Q33R

1: ST; 2: not specified; 3: conserved regulatory or receiver; 4: transmembrane domain 1; 5: transmembrane domain 2; 6: histidine kinase, adenylate cyclase,
methyl accepting proteins and phosphatases; 7: histidine kinase; 8: histidine kinase-like ATPase.
Abbreviations associated with AA: A: Alanine; C: Cysteine; D: Aspartate; E: Glutamate; F: Phenylalanine; G: Glycine; H: Histidine; I: Isoleucine; K: Lysine;
L: Leucine; M: Methionine; N: Asparagine; P: Proline; Q: Glutamine; R: Arginine; S: Serine; T: Threonine; V: Valine; W: Tryptophan; Y: Tyrosine.

The increased rate of PmrA dephosphorylation by PmrB vegetable), human (healthy or infected), rivers, seas, hospital
negates the possible effects of mutations in the phoPQ or sewage, vector insects, and public water facilities in different
mgrB genes. This may have been why there have been no re- Enterobacteriaceae species, including Enterobacter aerogenes,
ports on colistin resistance because of PhoPQ and MgrB sub- Salmonella spp, Klebsiella spp, etc. (Zhang et al. 2016, Jean-
stitutions (Janssen et al. 2020a). Although V108M and A182P not et al. 2017, Poirel et al. 2017, Yang et al. 2017, Zhao
substitutions in PhoP in strains derived from diseased pigs et al. 2017, Feng 2018, Torres et al. 2021). The first known
and the missense substitutions of E375K and N346K in PhoQ mrc-1 host was E. coli and mcr-1 positive E. coli (MCRPEC)
from human clinical specimens and rectal swabs isolated from has been a significant public health and environmental issue
healthy individuals have been documented in E. coli, their im- (Yang et al. 2017). A longitudinal multi-center study from
pacts on colistin resistance are unknown and not clinically 2008–2017 among Chinese patients showed that the preva-
confirmed (Cannatelli et al. 2017, Delannoy et al. 2017, Choi lence of MCRPEC had increased substantially from 0.42% to
et al. 2020, Binsker et al. 2021). 1.39%. However, a multicenter study in Italy showed that the
Also, in the case of PmrD, PmrAB, and PhoQP, alterations prevalence of PCRPEC had decreased by 0.3% (Jiang et al.
in several AAs were reported in isolates from animal samples, 2020).
and a missense mutation in K82 position, represents a hot Eleven genetic alleles of mcr-1 have been identified, sug-
spot, but their associations with colistin resistance have not gesting the possibility of further evolution of the gene. Mcr-
yet been determined (Kim et al. 2019b) (Table 2). A Mutation 1.1, mcr-1.2, mcr-1.3, mcr-1.4, mcr-1.5, mcr-1.7, mcr-1.8, and
in 33R and the V8A mutation in MgrB have been identified in mcr-1.9 have been reported in E. coli (Dominguez et al. 2019,
diseased pigs (Snyman et al. 2021). Alterations in other genes, Dadashi et al. 2021). Ten novel mcr-1 variants have been iden-
such as etk, encoding a tyrosine-kinase and mgrR, encoding a tified in Enterobacteriaceae so far, among which mcr-2, mcr-3,
can result in negative charged LPS in E. coli as well (Delan- and mcr-4, mcr-5, and mcr9 were found in E. coli recovered
noy et al. 2017). Also, it was found that mcr-negative E. coli from human or different animals (Table 3) (Xavier et al. 2016,
isolates from livestock in Korea have different AA changes in Cannatelli et al. 2017, Sun et al. 2018, Kieffer et al. 2019b,
PmrB, PhoP, PhoQ, MgrB, and/or PmrD. However, some of El-Sayed Ahmed et al. 2020, Tyson et al. 2020). These alleles
these polymorphic positions were also identified in colistin- have different degrees of AA similarity, but all of them encode
susceptible E. coli isolates. Additionally, colistin-resistant iso- PEtN transferases (Borowiak et al. 2017).
lates did not have any alterations in TCS PmrB and PhoPQ as The mcr genes are responsible for horizontally acquired col-
well as in their regulators MgrB and PmrD (Kim et al. 2019a). istin resistance. The mcr-1 encodes a cytoplasmic transmem-
brane protein which acts as phosphoethanolamine transferase
enzyme that adds PEtN to either the 1 or 4 -phosphate of
Plasmid-mediated resistance to colistin in E. Coli lipid A, resulting in less LPS negative net charge, like the chro-
In 2015, the first plasmid-mediated polymyxin resistance gene, mosomal mutations (Fig. 1) (Kim et al. 2019b). The mcr-1
mobile colistin resistance-1 (mcr-1), was identified in E. coli can spread rapidly under selective pressures (MacKinnon et
from food animals in China (Liu et al. 2016b). Since then, al. 2021). One study reported that the production of mcr-
mcr genes have been reported in E. coli strains from five 1 in E. coli leads to 4–8-fold increases in the minimum in-
continents (Asia, Europe, Africa, America, and Oceania) in hibitory concentration (MIC) of colistin; thus, solely the pro-
farms, wild animals, companion animals, food (meat and duction of mcr-1 is enough to impart colistin resistance in
8 Abavisani et al.

Table 3. Strain, harboring plasmid types, sources, and countries of novel mcr-1 variants profiles in E. coli.

mcr profile ST1 /Source Plasmid Type Country Reference

mcr-2 ST10 and ST167/Porcine IncX4 Belgium (Xavieret al. 2016)

and bovine diarrhea
mcr-3 ST744/Cattle IncF France (Haenniet al. 2018)
EC600-WJ1/Pig Feces IncHI2 China (Yinet al. 2017)
Ns 2 / Diseased pig Nm 3 Japan (Fukudaet al. 2018)
ZTA15/01169–1EB1/ IncHI2 Spain (Hernándezet al. 2017)
Bovine
ST155/ Agricultural soils Nm Algeria (Touatiet al. 2020)

ST1, ST10 and ST42/ IncHI2 and IncP South Korea (Mechessoet al. 2020)
Diseased pigs
ST132/ Dog feces, with IncP1 China (Duet al. 2020)

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mcr-1.1 co-occurrence
Ns/ Health calf, with triple IncQ1, IncX1 and IncY Belgium (Timmermanset al.
occurrence with mcr-5 and 2021)
mcr-1
mcr-4 ST10/ Diseased pig feces Nm Spain (Garcíaet al. 2018)
Mostly ST10/ Pigs ColE10-like and Spain (García-Meniñoet al.
diarrheagenic isolates Col8282-like 2019)
R4280 and R4278/ Piglets ColE10 Spain and Belgium (Carattoliet al. 2017)
Ns/ Healthy calf Mainly ColE10 and Belgium (Timmermanset al.
Col440II 2021)
Mcr-5 Ns/ Caecal contents of pigs pEC1066, pEC2380, Germany (Hammerlet al. 2018)
at slaughter and fecal pEC0674,
samples from pigs
ST10/ Diseased pig feces Nm Spain (Garcíaet al. 2018)
with concurrence with mcr-4
and mcr-1
PS8b/ Pig fecal sample Pps8B Spain (Kieffer et al. 2019a)
Mostly ST10/ Pigs pKP13a-like plasmid Spain (García-Meniñoet al.
diarrheagenic isolates 2019)
Ns/ Diseased pig Nm Japan (Fukudaet al. 2018)
ST113/ Healthy Chickens IncI1 Paraguay (Nesporovaet al. 2019)
Ns/ Health calf, with triple IncQ1, IncX1 and IncY Belgium (Timmermanset al.
occurrence with mcr-3 and 2021)
mcr-1
mcr-9 Ns/ Retail meat surveillance IncHI United States (Tysonet al. 2020)
D-ST69-O15:H6/ Human IncH2 Spain (Kiefferet al. 2019b)
fecal specimen

1: ST; 2: not specified; 3: not mentioned.

E. coli and other enterobacterial genera without additional Enterobacteriaceae isolates harboring plasmids carrying car-
resistance mechanisms (Poirel et al. 2017). However, due to bapenemase genes (Poirel et al. 2017).
the fitness cost of higher mcr-1 expression, mcr-1 expression mcr-1 is primarily located on plasmids and forms part of
is strictly regulated, and it is only found on plasmids with Tn6330 (ISApl1-mcr-1-pap2-ISApl1), a composite transpo-
relatively low copy counts (Bontron et al. 2016, Dénervaud son responsible for gene mobilization (Jiang et al. 2020). Sev-
Tendon et al. 2017). Colistin MIC in MCRPEC is moderate eral plasmid types harbor mcr genes, including IncI2, IncHI2,
(usually 2–8 mg L−1 ) compared to the chromosomal-mediated IncX4, IncP, IncF, and IncY type plasmids (Elbediwi et al.
colistin resistance, for example, increased expression of pm- 2019). Incl2 and IncX4 plasmids were reported to be the dom-
rAB (usually 8–256 mg L−1 ) (Yang et al. 2017). Crystal struc- inant vectors causing worldwide dissemination of mcr-1, with
tures of MCR1 have been studied extensively. It has been pro- more association with IncX4 (Liu et al. 2020). E. coli ST10,
posed that EtN and D-glucose substrate mimetics might serve the most frequent E. coli in different continents, and ST101,
as a helpful starting point for possible molecular inhibition of which is distributed among numerous hosts, are the significant
MCR-1 in drug design for colistin-based combination thera- clones carrying the mcr-1 gene (Elbediwi et al. 2019). In a re-
pies (Son et al. 2019). cent longitudinal study by Liuet al., prevalence of MCRPEC
Although the mcr-1 gene causes resistance to colistin, over- and its associated plasmids in E. coli strains isolated from live-
expression of mcr-1 changes cellular morphology, survival, stock in China was assessed. They reported a significant de-
immune stimulation, and virulence properties of the bacte- crease from 38%–45% in 2015–2016 to <2% in 2019. This
ria. It exerts toxic effects by decreasing cell growth rate, caus- decline may be attributable to the Chinese government’s ban
ing significant membrane degradation, and a moderate fitness of colistin use as a feed additive (in July 2016) in response to
loss. Other antimicrobial resistance genes carried by some of the 2015 mrc-1 report. Moreover, the toxic effect of MCR-1
these plasmids carrying the mcr-1 gene confer resistance to an- may partially account for the dramatic decline in prevalence
tibiotics including lactams, aminoglycosides, quinolones, fos- of MCR-1-bearing plasmids. Despite this, the prevalence of
fomycin, sulfonamides, and tetracyclines. More importantly, mcr-1-positive E. coli infections in China remains low (Jiang
the mcr-1 gene has been identified in highly drug-resistant et al. 2020).
Colistin resistance in the Escherichia coli 9

The widespread distribution of mcr genes in E. coli strains Acknowledgements

from animal and human sources represents a significant threat The authors would like to express their gratitude to the mem-
to public health worldwide. It has been observed that the bers of the Noncommunicable Diseases Research Center, Bam
prevalence of mcr-positive E. coli in animals and food prod- University of Medical Sciences, for their assistance.
ucts is dramatically higher than in human isolates, emphasiz-
ing the significance of foodborne transmission (Elbediwi et
al. 2019). Although the mcr-2 and mcr-9 genes were iden- Conflict of Interests Statement
tified mostly in the past 10 years, the most common mcr
No conflict of interest was declared.
gene, mcr-1, has been identified throughout time. In addition,
all mcr genes were detected in animal samples, and there is
evidence that animal sources contained mcr genes prior to Authors’ Contribution Statement
their identification (Luo et al. 2020). According to a Chinese
retrospective study, the consumption of colistin as a growth Mohammad Abavisani (Investigation, Visualization, Writ-
stimulant in the poultry industry may have been associated ing – original draft, Writing – review & editing), Narjess

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with the emergence of mcr genes (Shen et al. 2016). Some Bostanghadiri (Visualization, Writing – original draft), Hos-
evidence suggests that the mcr genes have originated in an- sein Ghahramanpour (Writing – original draft), Mansoor
imals. First, the high prevalence of mcr genes and signifi- Kodori (Conceptualization, Data curation, Investigation, Su-
cant selective colistin pressure in animals; second, the asso- pervision, Validation, Visualization, Writing – original draft,
ciation between the mcr-1 gene and ISApl1 element that was Writing – review & editing), Fariba Akrami (Writing – orig-
first discovered in the pig pathogen Actinobacillus pleurop- inal draft), Hadis Fathizadeh (Writing – original draft), Ali
neumoniae; and third, the presence of the floR gene in mcr- Hashemi (Data curation, Validation) and Mohsen Rastegari-
positive strains that confer resistance to florfenicol, a drug Pouyani (Data curation).
used only in veterinary medicine. As the plasmid harboring
mcr-1 is stable in the absence of colistin and is encoded by Data Availability Statement
MDR strains (which may have been co-selected with other
Data sharing is not applicable to this article as no datasets
antimicrobial elements), despite efforts to restrict its usage in
were generated or analyzed during the current study.
animals, mcr-1 will continue to spread worldwide (Liu and Liu
2018). Colistin is one of the last resort therapeutic options for
severe infection, mainly for carbapenem-resistant Enterobac- Reference
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