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. Author manuscript; available in PMC: 2020 May 23.
Published in final edited form as: Crit Rev Microbiol. 2019 May 23;45(2):131–161. doi: 10.1080/1040841X.2018.1492902

The rise and spread of mcr plasmid-mediated polymyxin resistance

Sue C Nang 1, Jian Li 1,*, Tony Velkov 2,*
PMCID: PMC6625916  NIHMSID: NIHMS1514705  PMID: 31122100

Abstract

Polymyxins are important lipopeptide antibiotics that serve as the last-line defense against multidrug-resistant (MDR) Gram-negative bacterial infections. Worryingly, the clinical utility of polymyxins is currently facing a serious threat with the global dissemination of mcr, plasmid-mediated polymyxin resistance. The first plasmid-mediated polymyxin resistance gene, termed as mcr-1 was identified in China in November 2015. Following its discovery, isolates carrying mcr, mainly mcr-1 and less commonly mcr-2 to -7, have been reported across Asia, Africa, Europe, North America, South America and Oceania. This review covers the epidemiological, microbiological and genomics aspects of this emerging threat to global human health. The mcr has been identified in various species of Gram-negative bacteria including Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Salmonella enterica, Cronobacter sakazakii, Kluyvera ascorbata, Shigella sonnei, Citrobacter freundii, Citrobacter braakii, Raoultella ornithinolytica, Proteus mirabilis, Aeromonas, Moraxella and Enterobacter species from animal, meat, food product, environment and human sources. More alarmingly is the detection of mcr in extended-spectrum-β-lactamases- and carbapenemases-producing bacteria. The mcr can be carried by different plasmids, demonstrating the high diversity of mcr plasmid reservoirs. Our review analyses the current knowledge on the emergence of mcr-mediated polymyxin resistance.

Keywords: mcr, polymyxin resistance, Gram-negative bacteria

Introduction

Polymyxins are cyclic lipopeptide antibiotics that were first discovered in the 1940s (Ainsworth et al. 1947; Benedict and Langlykke 1947; Stansly et al. 1947). Polymyxin B and colistin (polymyxin E) were introduced into clinical practice for the treatment of Gram-negative bacterial infections in 1959 (Ross et al. 1959). Their clinical usage was subsequently withdrawn due to high incidence of nephro- and neuro-toxicity, and also due to the introduction of ‘safer’ antimicrobial agents such as the β-lactams which were equally effective at the time (Fekety et al. 1962; Brown et al. 1970; Koch-Weser et al. 1970). However, over the last two decades the emergence of multidrug-resistant (MDR) Gram-negative bacteria that are resistant to all other antibiotics and paucity of novel antibiotics in the discovery pipeline have led to a resurgence of polymyxin usage in the clinic (Li et al. 2006). Albeit, an increasing incidence of polymyxin-resistant bacterial infections has been reported in both the nosocomial and community settings (Srinivas and Rivard. 2017). The primary mechanism of polymyxin resistance in Gram-negative bacteria involves the modification of lipid A of lipopolysaccharide (LPS), which is a major component of the outer membrane and the initial target of polymyxins. Polymyxin resistance due to modifications of lipid A with positively-charged phosphoethanolamine (pEtN) and/or 4-amino-4-deoxy-L-arabinose (L-Ara4N) was first reported by Vaara et al. (1981); such modifications result in reduced negative charge of the outer membrane and hence reduce the electrostatic interaction with polymyxins (Olaitan et al. 2014; Baron et al. 2016). The modification of lipid A by pEtN and L-Ara4N is mediated by eptA and arnBCADTEF, respectively, which are regulated by two-component systems (TCSs), PhoPQ and PmrAB (Olaitan et al. 2014). The inactivation of mgrB, a negative regulator of PhoPQ system in Klebsiella pneumoniae, can lead to the upregulation of PhoPQ, resulting in polymyxin resistance (Poirel et al. 2015). Secondary polymyxin resistance mechanisms independent of modification of lipid A include production of capsular polysaccharide, expression of efflux pumps and an increased expression of outer membrane proteins (Olaitan et al. 2014). Notably, all of the aforementioned mechanisms of polymyxin resistance are chromosomally-mediated (Olaitan et al. 2014; Baron et al. 2016). Polymyxin resistance in K. pneumoniae and Acinetobacter baumannii is more commonly chromosomal-mediated, and occurs at a higher prevalence in current clinical settings, particularly in Greece and Italy (Giamarellou 2016). On the other hand, mcr is the main polymyxin resistance determinant in Escherichia coli and high prevalence remains in agriculture globally, especially in China. This is coincident with high polymyxin consumption and usage in the aforementioned countries (Giamarellou 2016; Liu YY et al. 2016).

A plasmid-mediated polymyxin resistance gene named mcr-1 was first reported in November 2015 (Liu YY et al. 2016). The emergence of plasmid-mediated polymyxin resistance is a matter of great concern due to the potential for rapid horizontal transfer. The mcr-1 encodes for pEtN transferase enzyme (MCR-1) which catalyzes the addition of pEtN to the phosphate groups in lipid A (Liu YY et al. 2016; Liu YY et al. 2017). The modification of lipid A with pEtN is not a novel mechanism of polymyxin resistance, as this has been frequently associated with the chromosomal gene, eptA (pmrC) (Olaitan et al. 2014; Baron et al. 2016; Huang J et al. 2017). However, the transferability of mcr is of considerable concern due to the potential of MDR Gram-negative bacteria to acquire mcr-harboring plasmids, negating antimicrobial therapy with the important last-line polymyxins.

To date, several other MCR have been identified, including MCR-2, -3, -4, -5, -6 and -7, which share 81%, 32.5%, 34%, 36.1%, 83% and 35% in the amino acid sequence identity, respectively, with MCR-1 (cf. Supplementary information Table S1) (Xavier et al. 2016; AbuOun et al. 2017, Borowiak, Fischer, et al. 2017; Carattoli et al. 2017; Yin et al. 2017; Yang et al. 2018). An additional minor variant was reported for each of MCR-2, -4 and -5, whereas a greater number of minor variants were identified for MCR-1 (11 variants) and MCR-3 (10 variants) (cf. Supplementary information Table S2). It should be noted that mcr-6 (deposited in Genbank in 2018; accession number: MF176240) was described as mcr-2.2 in the study published in 2017 (AbuOun et al. 2017).

Epidemiology

Time-line of mcr discovery

From the time-line diagram (Figure 1), we can clearly see the vast increase in the detection of mcr-positive isolates from various countries dating from 2009 onwards. Retrospective surveillance studies on stored bacterial isolates revealed that the earliest mcr (more specifically mcr-1) was identified from chicken in the 1980s in China, when colistin was started being used for farming purposes (Shen et al. 2016). It was then followed by the identification of mcr from cattle in 2004 (Italy; mcr-1) and veal calves which were raised at local farms in 2005 (France; mcr-1) (Haenni et al. 2016). The earliest mcr-positive bacterial strain from humans was a Shigella sonnei isolated from a hospitalized child in 2008 (Vietnam; mcr-1) (Thanh et al. 2016). It is also important to note that to date, the earliest occurrence of mcr in isolates from wild animals (fish; Aeromonas allosaccharophila; mcr-3.6) and environmental samples (seawater; E. coli; mcr-1) was in 2005 and 2010, respectively (Jørgensen et al. 2017; Eichhorn et al. 2018).

Figure 1.

Figure 1.

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Time-line of the first identification of mcr in each country.

Among mcr-2 to -7, the earliest mcr-3 (more specifically mcr-3.6) was discovered in 2005 (Eichhorn et al. 2018); whereas mcr-2 (2009), -4 (2013), -5 (2011), -6 (2015) and -7 (2014) were only identified in strains collected over the past decade (Carattoli et al. 2017; Fisher et al. 2017; AbuOun et al. 2018; Borowiak, Eichhorn et al. 2018; Yang et al. 2018). More retrospective studies involving mcr genes should be conducted. Generally, it is evident that mcr has already existed for at least three decades.

Geographical spread of mcr

Since the first discovery of the mcr, a number of epidemiological studies have been carried out worldwide (Skov and Monnet 2016). The mcr has been detected in 47 different countries across six continents: Asia (China, Japan, Laos, Vietnam, Malaysia, Singapore, Cambodia, Bahrain, Taiwan, Hong Kong, Thailand, South Korea, Russia, Pakistan, United Arab Emirates, Saudi Arabia and Oman), Europe (Austria, Estonia, UK, The Netherlands, Norway, Spain, Germany, France, Belgium, Denmark, Italy, Poland, Portugal, Russia, Switzerland, Sweden, Lithunia and Hungary), Africa (Algeria, Egypt, Tunisia, Morocco and South Africa), North America (USA and Canada), South America (Colombia, Argentina, Brazil and Ecuador) and Oceania (New Caledonia and Australia) (cf. Table 1 and Figure 2). Among these countries, mcr was identified from human sources in 44 countries, livestock in 21 countries, meat and food products in 13 countries and other sources (including pet/exotic/wild animals and environment) in 11 countries. The only countries in which mcr have been reported from livestock but not humans are Estonia and Tunisia. No trace of mcr has been detected in Antarctica. To date, China, where the first mcr was detected, has the highest prevalence of mcr-positive isolates (cf. Figure 2). This could be due to the fact that polymyxins were heavily used and extensive studies on mcr have been conducted in China.

Table 1.

Characterization of mcr-harboring bacteria.

Category Country Year Species Source No. of isolate Reference
Human Algeria 2011 E. coli Urine 1 Berrazeg et al. 2016
E. coli Sperm culture 1 Yanat et al. 2016
2013 E. coli Rectum 7 Leangapichart et al. 2016
K. pneumoniae Rectum 1 Leangapichart et al. 2016
2014 E. coli Rectum 1 Leangapichart et al. 2016
Argentina 2012 E. coli Blood (n=1 mcr-1.5)
Urine (n=1)		 2 Rapoport et al. 2016; Tijet et al. 2017
2013 E. coli Abdominal (n=1 mcr-1.5)
Blood (n=1)		 2 Rapoport et al. 2016; Tijet et al. 2017
2015 E. coli Urine (n=2 mcr-1.5)
Blood (n=1)
Bone (n=1)		 4 Rapoport et al. 2016; Tijet et al. 2017
2016 E. coli Abscess 1 Rapoport et al. 2016
Australia 2011 E. coli Urine 1 Ellem et al. 2017
2013 E. coli Urine 1 Ellem et al. 2017
Austria 2016 E. coli Fecal sample 1 Hartl et al. 2017
Bahrain 2015 E. coli Wound (n=1)
Urine (n=1)		 2 Sonnevend et al. 2016
2015 E. coli Groin and peri-rectal 4 Snesrud et al. 2017
Belgium 2014 – 2015 E. coli NA 1 Castanheira et al. 2016
2015 E. coli Pus 1 Huang TD et al. 2017
Brazil 2014 – 2015 E. coli NA 1 Castanheira et al. 2016
2015 E. coli Rectum (n=2)
Blood (n=1)		 3 Conceição-Neto et al. 2017
2016 K. pneumoniae Urine 1 Aires et al. 2017
2016 E. coli Wound 1 Fernandes, McCulloch, et al. 2016
Cambodia 2012 E. coli Fecal sample 1 Stoesser et al. 2016
Canada 2010 E. coli Blood 2 Walkty et al. 2016
2011 E. coli Gastrostomy tube site, rectum 1 Mulvey et al. 2016
2015 – 2016 E. coli Urine 1 Payne et al. 2016
China 2011 and earlier NA Fecal sample (Human microbiome) 27 Hu Y et al. 2016; Ruppé et al. 2016
2011 E. coli Abdominal fluid 1 Wang X et al. 2017
K. pneumoniae Wound 1 Wang X et al. 2017
2012 E. coli Blood (n=8)
Urine (n=1)
Rectum (n=25)		 34 Lima Barbieri et al. 2017; Quan et al. 2017; Wang X et al. 2017; Wang Y et al. 2017
K. pneumoniae Blood 3 Wang X et al. 2017
S. enterica Enteritidis NA 2 Cui et al. 2017
S. enterica Typhimurium NA 1 Cui et al. 2017
2013 E. coli Blood (n=11)
Drainage fluid (n=1)
Abdominal fluid (n=4)
Sputum (n=1)
Urine (n=1)		 18 Quan et al. 2017; Wang X et al. 2017; Wang Y et al. 2017
S. enterica NA 1 Cui et al. 2017
S. enterica Typhimurium NA 5 Cui et al. 2017
2014 E. coli Urine (n=5)
Sputum (n=3)
Drainage fluid (n=9)
Bile (n=2)
Ascites (n=3)
Wound (n=1)
Blood (n=22)
Pus (n=1)		 46 Du et al. 2016; Liu YY et al. 2016; He QW et al. 2017; Quan et al. 2017; Wang X et al. 2017; Wang Y et al. 2017
K. pneumoniae Urine (n=1)
Sputum (n=2)
Blood (n=1)		 4 Liu YY et al. 2016; Quan et al. 2017
Enterobacter aerogenes Vaginal secretion 1 Zeng et al. 2016
Enterobacter cloacae Urine 1 Zeng et al. 2016
S. enterica Rectum (n=1mcr-1.6)
NA (n=3)		 4 Cui et al. 2017; Lu et al. 2017
2014 – 2015 E. coli NA 2 Zhang R et al. 2017
2015 E. coli Abscess (n=2)
Fecal sample (n=63)
Blood (n=10)
Urine (n=20)
Ascites (n=1)
Bile (n=8)
Catheter (n=2)
Drainage fluid (n=7)
Pus (n=1)
Respiratory tract (n=1)
Secretion (n=8)
Sputum (n=13)
Wound (n=1)		 137 Du et al. 2016; Gu et al. 2016; Ye et al. 2016; Yu H et al. 2016; Zhang R et al. 2016; Zhang XF et al. 2016; He QW et al. 2017; Tian et al. 2017; Wang Y et al. 2017
K. pneumoniae Fecal sample (n=2)
Surgical wound (n=1)
Peritoneal fluid (n=1)
Sputum (n=1)		 5 Du et al. 2016; Gu et al. 2016; Tian et al. 2017; Wang Y et al. 2017
S. enterica Typhimurium NA 16 Cui et al. 2017
2016 E. coli Fecal sample 34 Zhong et al. 2016; Hu et al. 2017; Zheng et al. 2017
K. pneumoniae Sputum 4 Tian et al. 2017
Citrobacter freundii Fecal sample 1 Hu et al. 2017
2017 E. coli mcr-3.5 Abdominal abscess 1 Liu L et al. 2017
NA E. coli Blood 2 Zheng et al. 2016
K. pneumoniae NA 13 Wang Y et al. 2017
Enterobacter cloacae NA 1 Wang Y et al. 2017
Enterobacter aerogenes NA 1 Wang Y et al. 2017
Colombia 2013 E. coli Leg secretion (n=1)
Blood (n=1)		 2 Saavedra et al. 2017
2015 S. enterica Typhimurium Fecal sample (n=1)
Urine (n=1)		 2 Saavedra et al. 2017
2016 E. coli Urine (n=2)
Vaginal secretion (n=1)
Abdominal abscess (n=1)
Toe tissue (n=1)
NA (n=1)		 6 Saavedra et al. 2017
K. pneumoniae Blood 1 Saavedra et al. 2017
S. enterica Typhimurium Fecal sample 1 Saavedra et al. 2017
Denmark 2009 S. enterica Typhimurium mcr-3 NA 1 Litrup et al. 2017
2010 S. enterica O:4,5,12;H:i:- mcr-3 NA 1 Litrup et al. 2017
2011 S. enterica O:4,5,12;H:i:- mcr-3 NA 2 Litrup et al. 2017
2012 S. enterica Typhimurium mcr-3 NA 2 Litrup et al. 2017
S. enterica O:4,5,12;H:i:- mcr-3 NA 1 Litrup et al. 2017
2014 S. enterica Typhimurium NA 2 Torpdahl et al. 2017
E. coli mcr-3 Blood 1 Roer et al. 2017
2015 E. coli Blood 1 Hasman et al. 2015
S. enterica Typhimurium NA 2 Torpdahl et al. 2017
S. enterica O:4,5,12;H:i:- mcr-3 NA 1 Litrup et al. 2017
2016 S. enterica O:4,5,12;H:i:- mcr-3 NA 1 Litrup et al. 2017
2017 S. enterica O:4,5,12;H:i:- mcr-3 NA 1 Litrup et al. 2017
Ecuador 2016 E. coli Peritoneal fluid 1 Ortega-Paredes et al. 2016
Egypt 2015 E. coli Sputum 1 Elnahriry et al. 2016
France 2012 – 2013 K. pneumoniae Fecal sample 2 Rolain et al. 2016
2016 E. coli Fecal sample 1 Beyrouthy et al. 2017
Germany 2014 E. coli Wound 1 Falgenhauer, Waezsada, Yao, et al. 2016
2014 – 2015 E. coli NA 5 Castanheira et al. 2016
2016 E. coli Urine 1 Fritzenwanker et al. 2016
Hungary 2011 E. coli Blood 1 Juhász et al. 2017
Hong Kong 2014 – 2015 E. coli NA 1 Castanheira et al. 2016
2015 – 2016 E. coli Blood (n=2)
Fecal sample (n=1)
Urine (n=1)		 4 Wong et al. 2016
2015 – 2016 Enterobacter cloacae Fecal sample 1 Wong et al. 2016
Italy 2012 – 2015 S. enterica NA 10 Carnevali et al. 2016
2013 E. coli Urine 1 Cannatelli et al. 2016
2014 E. coli Urine, surgical wound 3 Cannatelli et al. 2016
K. pneumoniae mcr-1.2 Rectum 1 Di Pilato et al. 2016
2015 E. coli Urine (n=4)
Intestinal colonization (n=3)		 7 Cannatelli et al. 2016; Giufrè et al. 2016
2014 – 2015 E. coli NA 4 Castanheira et al. 2016
2016 E. coli Blood 2 Corbella et al. 2017
S. enterica Typhimurium mcr-4.2 Fecal sample 2 Carretto et al. 2018
2017 E. coli Blood 1 Corbella et al. 2017
Japan 2017 E. coli Fecal sample 1 Tada, Uechi, et al. 2017
Kingdom of Saudi Arabia 2012 E. coli Blood 1 Sonnevend et al. 2016
Laos 2012 E. coli Fecal sample 6 Olaitan et al. 2016
2012 K. pneumoniae Fecal sample 4 Rolain et al. 2016
Malaysia 2013 E. coli Urine 1 Yu, Ang, Chin, et al. 2016
2014 – 2015 E. coli NA 1 Castanheira et al. 2016
Morocco 2014 E. coli Rectum 2 Leangapichart et al. 2016
New Caledonia 2014 E. coli Ascites (n=1)
Gastric fluid (n=1)		 2 Robin et al. 2016
Norway 2014 E. coli NA 1 Solheim et al. 2016
Oman 2016 E. coli Blood 1 Mohsin et al. 2017
Pakistan 2016 E. coli Wound 1 Mohsin et al. 2016
Poland 2015 E. coli Urine 1 Izdebski et al. 2016
Portugal 2011 – 2012 S. enterica 1,4,[5],12:i:- Blood, fecal sample 4 Campos et al. 2016
2016 E. coli Urine 1 Tacão et al. 2017
Russia 2014 – 2015 E. coli NA 1 Castanheira et al. 2016
Singapore 2016 E. coli Urine 2 Teo et al. 2016
2016 K. pneumoniae Urine 1 Teo et al. 2016
South Africa 2014 – 2016 E. coli Blood (n=1)
Wound (n=1)
Pus (n=1)
Urine (n=6)		 9 Coetzee et al. 2016; Poirel, Kieffer, Brink, et al. 2016
2016 E. coli Urine (n=9)
Superficial abdominal swab (n=1)		 10 Newton-Foot et al. 2017
2016 K. pneumoniae Sputum (n=2)
Urine (n=2)		 4 Newton-Foot et al. 2017
2016 K. oxytoca Superficial abdominal swab 1 Newton-Foot et al. 2017
South Korea 2014 – 2015 E. coli Blood 1 Kim et al. 2017
Spain 2012 E. coli Blood 1 Prim et al. 2016
2013 E. coli Sputum (n=3)
Blood (n=4)
Urine (n=1)		 8 Prim et al. 2016
2014 E. coli Urine (n=2)
Surgical wound (n=1)		 3 Prim et al. 2016
2015 E. coli Urine 3 Prim et al. 2016
2014 – 2015 E. coli NA 3 Castanheira et al. 2016
2016 E. coli Peritoneal fluid (n=1)
Sputum (n=1)		 2 Ortiz de la Tabla et al. 2016; Sánchez-Benito et al. 2017
2012 – 2015 E. coli Blood (n=5), urine (n=6), sputum (n=3), surgical wound secretion (n=1) 15 Prim et al. 2017
Sweden 2013 E. coli Fecal sample 1 Vading et al. 2016
Switzerland 2015 E. coli Urine (n=1)
Fecal sample (n=3, 1mcr-1.2)
Blood (n=2)		 7 Bernasconi et al. 2016; Nordmann, Lienhard, et al. 2016; Poirel, Kieffer, Liassine, et al. 2016; Donà, Bernasconi, Kasraian, et al. 2017
2016 E. coli Urine (n=1)
Fecal sample (n=2)		 3 Zurfluh et al. 2017
Taiwan 2010 E. coli Sputum 1 Kuo et al. 2016
2012 E. coli Urine 2 Kuo et al. 2016
2014 E. coli Ascites (n=1)
Abscess (n=2)
Blood (n=3)
Urine (n=5)		 11 Kuo et al. 2016
S. enterica Typhimurium NA 5 Chiou et al. 2017
2015 S. enterica Typhimurium NA 3 Chiou et al. 2017
S. enterica Newport NA 1 Chiou et al. 2017
S. enterica Albany NA 1 Chiou et al. 2017
NA E. coli Urine 1 Lai et al. 2017
Thailand 2012 E. coli Fecal sample 2 Olaitan et al. 2016
2014 – 2015 E. coli Urine 1 Runcharoen et al. 2017
2016 E. coli Urine 1 Paveenkittiporn et al. 2016
The Netherlands 2012 – 2013 E. coli Fecal sample 6 Arcilla et al. 2016
2014 E. coli Fecal sample 1 Nijhuis et al. 2016
2015 E. coli Fecal sample 2 Nijhuis et al. 2016
2014 – 2015 E. coli Fecal sample 1 Terveer et al. 2017
The United States 2014 E. coli Urine 1 Mediavilla et al. 2016
2015 E. coli Urine 1 Castanheira et al. 2016
2015 E. coli Blood 1 Macesic et al. 2017
2016 E. coli Urine 1 McGann et al. 2016
2016 E. coli Fecal sample 1 Vasquez et al. 2016
The United Kingdom 2012 S. enterica Typhimurium Fecal sample 1 Doumith et al. 2016
2013 E. coli Fecal sample (n=1)
Blood (n=1)		 2 Doumith et al. 2016
2014 E. coli Blood 1 Doumith et al. 2016
2014 S. enterica Typhimurium Fecal sample 2 Doumith et al. 2016
2014 S. enterica Virchow Fecal sample 1 Doumith et al. 2016
2015 S. enterica Typhimurium Fecal sample 5 Doumith et al. 2016
2015 S. enterica Paratyphi Fecal sample 1 Doumith et al. 2016
United Arab Emirates 2013 E. coli Blood 1 Sonnevend et al. 2016
Vietnam 2008 Shigella sonnei Fecal sample 1 Thanh et al. 2016
2012 – 2013 E. coli Rectum 3 Trung et al. 2017
2014 E. coli Urine (n=1)
Pus (n=1)		 2 Tada, Nhung, et al. 2017
Livestock Algeria 2015 E. coli Chicken 1 Olaitan et al. 2016
Brazil 2012 E. coli Pig 2 Fernandes, Moura, et al. 2016
2013 E. coli Chicken 14 Fernandes, Moura, et al. 2016
2015 E. coli Chicken 10 Lentz et al. 2016
Belgium 2011 – 2012 E. coli Calf (n=6)
Pig (n=7)
Calf (n=1mcr-2)
Pig (n=2mcr-2)		 16 Malhotra-Kumar, Xavier, Das, Lammens, Butaye, et al. 2016; Xavier et al. 2016
2013 E. coli Cattle (n=1)
Pig (n=1)		 2 El Garch et al. 2016
2015 – 2016 E. coli mcr-4 Pig 2 Carattoli et al. 2017
China 1980s E. coli Chicken 3 Shen et al. 2016
2004 – 2006 E. coli Chicken 8 Shen et al. 2016
2007 S. enterica Typhimurium Chicken 1 Li XP et al. 2016
2008 S. enterica Typhimurium Pig 2 Li XP et al. 2016
2009 E. coli Chicken 6 Shen et al. 2016
S. enterica Typhimurium Pig 1 Li XP et al. 2016
2010 E. coli Chicken 13 Shen et al. 2016; Yang YQ et al. 2017
S. enterica Typhimurium Duck 1 Li XP et al. 2016
2011 E. coli Chicken (n=30)
Pig (n=3)		 33 Li Z et al. 2016; Shen et al. 2016; Yang YQ et al. 2017
2012 E. coli Pig (n=33)
Chicken (n= 42)		 75 Li Z et al. 2016; Liu YY et al. 2016; Shen et al. 2016; Lima Barbieri et al. 2017; Yang YQ et al. 2017
2013 E. coli Pig (n=69)
Chicken (n=39) Chicken (n=1mcr-1.3)		 109 Li Z et al. 2016; Liu YY et al. 2016; Shen et al. 2016; Lima Barbieri et al. 2017; Wang X et al. 2017; Yang YQ et al. 2017
2014 E. coli Pig (n=67)
Chicken (n=26)		 93 Liu YY et al. 2016; Shen et al. 2016; Lima Barbieri et al. 2017; Yang YQ et al. 2017
Citrobacter freundii Pig 1 Li XP et al. 2017
K. pneumoniae mcr-7 Chicken 1 Yang et al. 2018
2010 – 2015 K. pneumoniae Chicken (n=7) Chicken (n=2mcr-7) 9 Yang et al. 2018
2014 – 2015 E.coli Pig 35 Li R et al. 2017
S. enterica Chicken 4 Yang YQ et al. 2016
2015 E. coli Duck (n=2)
Chicken (n=66)
Cattle (n=1)
Pig (n=1mcr-3)		 70 Liu BT et al. 2016; Yang RS et al. 2016; He T et al. 2017; Yang YQ et al. 2017; Yi et al. 2017; Yin et al. 2017
Aeromonas veronii mcr-3.3 Chicken 1 Ling et al. 2017
Cronobacter sakazakii Chicken (n=2) 2 Liu BT et al. 2016
2015 – 2016 S. enterica Chicken (n=6)
Pig (n=6)		 12 Ma et al. 2017
2017 Aeromonas caviae mcr-3.10 Duck 1 Wang et al. 2018
E. coli mcr-3.10 Duck 1 Wang et al. 2018
Proteus mirabilis mcr-3.10 Duck 1 Wang et al. 2018
Egypt 2010 E. coli Chicken 4 Lima Barbieri et al. 2017
2014 E. coli Cattle 1 Khalifa et al. 2016
Estonia 2013 E. coli Pig 3 Brauer et al. 2016
France 2005 – 2014 E. coli Calf 106 Haenni et al. 2016
2004 E. coli Cattle 1 El Garch et al. 2016
2005 E. coli Cattle 1 El Garch et al. 2016
2006 E. coli Pig 2 El Garch et al. 2016
2007 E. coli Cattle (n=2)
Pig (n=1)		 3 Brennan et al. 2016; El Garch et al. 2016
2008 E. coli Cattle (n=1)
Pig (n=1)		 2 El Garch et al. 2016
2009 E. coli Pig 3 El Garch et al. 2016
2010 E. coli Cattle (n=4)
Pig (n=5)		 9 El Garch et al. 2016
2011 E. coli Cattle (n=1)
Pig (n=2)		 3 El Garch et al. 2016; Perrin-Guyomard et al. 2016
2012 E. coli Pig 3 El Garch et al. 2016
2013 E. coli Chicken (n=3)
Pig (n=4)		 7 El Garch et al. 2016; Perrin-Guyomard et al. 2016
S. enterica 1,4,[5],12:i:- Chicken 1 Webb et al. 2016
2014 E. coli Chicken (n=4)
Turkey (n=14)
Pig (n=1)		 19 El Garch et al. 2016; Perrin-Guyomard et al. 2016
Germany 2008 S. enterica Paratyphi B Chicken 1 Borowiak, Hammerl, et al. 2017
2010 – 2011 E. coli Pig 3 Falgenhauer, Waezsada, Yao, et al. 2016
S. enterica Pig 1 El Garch et al. 2016
2010 E. coli Chicken (n=8)
Turkey (n=30)
Calf (n=15)
Pig (n=1)		 54 El Garch et al. 2016; Irrgang et al. 2016
2011 E. coli Laying hen (n=2)
Chicken (n=17)
Turkey (n=33)
Pig (n=13)		 65 Irrgang et al. 2016
2011 – 2012 E. coli Pig farm (boot swab and fecal sample) 43 Roschanski et al. 2017
2012 Aeromonas media mcr-3.7 Turkey 1 Eichhorn et al. 2018
E. coli Turkey (n=63)
Calf (n=5)		 68 Irrgang et al. 2016
S. enterica Paratyphi B mcr-5 Poultry 8 Borowiak, Fischer, et al. 2017
2013 E. coli Chicken 52 Irrgang et al. 2016
2014 E. coli Laying hens(n=1)
Chicken (n=22)
Turkey (n=37)		 60 Irrgang et al. 2016
2015 E. coli Calf (n=1)
Pig (n=11)		 12 Irrgang et al. 2016
2016 E. coli Pig 11 Schirmeier et al. 2017
Italy 2004 E. coli Cattle 2 El Garch et al. 2016
2006 E. coli Cattle 1 El Garch et al. 2016
2007 E. coli Pig 3 El Garch et al. 2016
2008 E. coli Pig 1 El Garch et al. 2016
2010 – 2011 S. enterica Pig 2 El Garch et al. 2016
2011 E. coli Pig 1 El Garch et al. 2016
2012 E. coli Pig 1 El Garch et al. 2016
2013 S. enterica Typhimurium mcr-4 Pig 1 Carattoli et al. 2017
2014 E. coli Pig 1 El Garch et al. 2016
2012 – 2015 S. enterica Poultry (n=2)
Pig (n=9)		 11 Carnevali et al. 2016
2015 – 2016 E. coli Pig 37 Curcio et al. 2017
2016 E. coli Pig 1 Pulss et al. 2017
Japan 2007 – 2014 E. coli Pig 90 Kusumoto et al. 2016
2008 E. coli Pig 2 Kawanishi et al. 2016; Suzuki et al. 2016
2010 E. coli Pig 5 Kawanishi et al. 2016; Suzuki et al. 2016
2011 E. coli Cattle 1 Kawanishi et al. 2016
2012 E. coli Pig (n=5)
Cattle (n=2)
Chicken (n=2)		 9 Kawanishi et al. 2016
2013 E. coli Pig (n=3)
Cattle (n=1)
Chicken (n=2)		 6 Kawanishi et al. 2016
S. enterica Typhimurium Pig 1 Suzuki et al. 2016
2012 – 2013 E. coli Cattle 4 Suzuki et al. 2016
2014 E. coli Pig (n=7)
Cattle (n=1)
Chicken (n=10)		 18 Kawanishi et al. 2016
Laos 2012 E. coli Pig 3 Olaitan et al. 2016
Malaysia 2013 E. coli Chicken (n=5)
Pig (n=1)		 6 Petrillo et al. 2016; Yu, Ang, Chin, et al. 2016
South Africa 2015 E. coli Chicken 19 Perreten et al. 2016
South Korea 2013 E. coli Chicken 1 Lim et al. 2016
2014 E. coli Chicken 6 Lim et al. 2016
2015 E. coli Chicken (n=3)
Pig (n=1)		 4 Lim et al. 2016
Spain 2009 S. enterica Typhimurium Pig 1 Quesada et al. 2016
M. pluranimalium mcr-2.2 Pig 1 AbuOun et al. 2017
2010 S. enterica Typhimurium Pig 1 Quesada et al. 2016
S. enterica Rissen Pig 1 Quesada et al. 2016
2011 E. coli Pig 1 Quesada et al. 2016
S. enterica Typhimurium Pig 1 Quesada et al. 2016
2013 E. coli Pig 1 Quesada et al. 2016
2014 E. coli Turkey 3 Quesada et al. 2016
2015 E. coli Cattle (n=4, 1mcr-3.2) 5 Hernández et al. 2017
2015 – 2016 E. coli mcr-4 Pig 9 Carattoli et al. 2017
Taiwan 2012 S. enterica Typhimurium Pig 1 Chiou et al. 2017
2013 S. enterica Typhimurium Pig (n=3)
Chicken (n=2)		 5 Chiou et al. 2017
S. enterica Anatum Pig 3 Chiou et al. 2017
The Netherlands 2010 – 2011 E. coli Calf (n=15)
Chicken (n=2)
Turkey (n=1)		 18 Veldman et al. 2016
2012 – 2013 E. coli Chicken 8 Veldman et al. 2016
The United Kingdom 2014 M. porci mcr-1.10 Pig 1 AbuOun et al. 2017
2015 E. coli Pig 4 Anjum et al. 2016; Duggett et al. 2016
S. enterica Typhimurium Pig 1 Anjum et al. 2016
M. pluranimalium mcr-6 Pig 1 AbuOun et al. 2017
The United States 2016 E. coli Pig 3 Meinersmann, Ladely, Bono, et al. 2016; Meinersmann, Ladely, Plumblee, et al. 2016
Tunisia 2015 E. coli Chicken 37 Grami et al. 2016
Vietnam 2012 – 2013 E. coli Chicken 19 Trung et al. 2017
2013 – 2014 E. coli Chicken (n=20)
Pig (n=17)		 37 Nguyen et al. 2016
2014 – 2015 E. coli Pig 9 Malhotra-Kumar, Xavier, Das, Lammens, Hoang, et al. 2016
Meat and food product Brazil 2016 E. coli Chicken meat 8 Monte et al. 2017
Canada 2010 E. coli Beef (Unknown origin) 2 Mulvey et al. 2016
China 2011 E. coli Pork (n=3)
Chicken meat(n=10)		 13 Liu YY et al. 2016
2013 E. coli Pork (n=11)
Chicken meat(n=4)		 15 Liu YY et al. 2016
2014 E. coli Pork (n=29)
Chicken meat (n=21)		 50 Liu YY et al. 2016
2015 – 2016 E. coli Retail food sample 109 Liu X et al. 2017
S. enterica Chicken meat (n=5)
Pork (n=5)		 10 Ma et al. 2017
2015 E. coli Vegetable 3 Luo et al. 2017
Raoultella ornithinolytica Vegetable 2 Luo et al. 2017
2016 E. coli Vegetable 4 Luo et al. 2017
Denmark 2012 E. coli Chicken meat(imported from Europe) 3 Hasman et al. 2015
2013 E. coli Chicken meat (imported from Europe) 1 Hasman et al. 2015
2014 E. coli Chicken meat(imported from Europe) 1 Hasman et al. 2015
France 2012 S. enterica Paratyphi B Chicken breast (n=1)
Ready-to-cook guinea fowl pie (n=1)		 2 Webb et al. 2016
2013 S. enterica Derby Chipolata sausage 1 Webb et al. 2016
Italy 2013 – 2015 S. enterica Pork 4 Carnevali et al. 2016
Japan 2015 E. coli Chicken meat 1 Ohsaki et al. 2017
Taiwan 2012 E. coli Beef 1 Kuo et al. 2016
2013 E. coli Chicken meat 6 Kuo et al. 2016
2015 E. coli Chicken meat (n=9)
Pork (n=2)		 11 Kuo et al. 2016
The Netherlands 2009 E. coli Chicken meat(Unknown origin) 1 Kluytmans-van den bergh et al. 2016
2013 S. enterica Anatum Turkey meat (imported) 1 Veldman et al. 2016
2014 E. coli Chicken meat(imported from Europe) 2 Kluytmans-van den bergh et al. 2016
2015 S. enterica Schwarzengrund Turkey meat (imported) 1 Veldman et al. 2016
E. coli Chicken meat 33 Schrauwen et al. 2017
K. pneumoniae Chicken meat 2 Schrauwen et al. 2017
2010 – 2015 S. enterica Java Chicken meat (local) 11 Veldman et al. 2016
The United Kingdom 2014 S. enterica Paratyphi B Poultry meat (imported from Europe) 2 Doumith et al. 2016
Germany 2010 E. coli Turkey meat 17 Irrgang et al. 2016
2011 E. coli Chicken meat 14 Irrgang et al. 2016
S. enterica Paratyphi B mcr-5 Chicken meat 1 Borowiak, Fischer, et al. 2017
2012 E. coli Chicken breast (n=1)
Turkey hen Schnitzel (n=1)
Turkey meat (n=30)
Beef (n=2)		 34 Falgenhauer, Waezsada, Gwozdzinski, et al. 2016; Irrgang et al. 2016
S. enterica Paratyphi B mcr-5 Chicken meat 1 Borowiak, Fischer, et al. 2017
2013 E. coli Turkey meat (n=1)
Chicken meat (n=10)		 11 Falgenhauer, Waezsada, Gwozdzinski, et al. 2016; Irrgang et al. 2016
S. enterica Paratyphi B mcr-5 Chicken meat 1 Borowiak, Fischer, et al. 2017
2014 E. coli Chicken meat (n=1)
Turkey meat (n=10)		 11 Irrgang et al. 2016
Portugal 2011 S. enterica Typhimurium Food product (originated from swine and poultry) 3 Figueiredo et al. 2016; Tse and Yuen 2016
2012 S. enterica Typhimurium Food product (originated from cattle) 1 Figueiredo et al. 2016
2014 – 2015 S. enterica 1,4,[5],12:i:- Pork meat/carcass 5 Campos et al. 2016
S. enterica Rissen Pork carcass 2 Campos et al. 2016
Switzerland 2014 E. coli Vegetable (imported from Thailand and Vietnam) 2 Zurfuh et al. 2016
Chicken meat (imported from Germany) 4 Donà, Bernasconi, Pires, et al. 2017
2015 E. coli Chicken meat (imported from Germany and Italy) 2 Zogg et al. 2016
2016 E. coli Chicken meat (imported from Germany and Italy)
Turkey meat (imported from Germany and Italy)		 14 Zurfluh, Buess, et al. 2016; Donà, Bernasconi, Pires, et al. 2017
Other animal Argentina 2012 E. coli Kelp gulls 5 Liakopoulos et al. 2016
Brazil 2013 E. coli Magellanic
penguins		 1 Sellera et al. 2016
China 2016 E. coli Dog (n=4)
Cat (n=2)		 6 Zhang XF et al. 2016
Germany 2005 Aeromonas allosaccharophila mcr-3.6 Fish 1 Eichhorn et al. 2018
2006 Aeromonas hydrophila mcr-3.8, mcr-3.9 Fish 1 Eichhorn et al. 2018
2008 Aeromonas jandaei mcr-3.8 Fish 1 Eichhorn et al. 2018
Lithuania 2016 E. coli European herring gulls 1 Ruzauskas and Vaskeviciute 2016
Vietnam 2013 – 2014 E. coli Asian grass lizard 2 Unger et al. 2016
Environment Brazil 2016 E. coli Sea water 3 Fernandes et al. 2017
China 2015 Kluyvera ascorbata Hospital sewage 1 Zhao and Zong 2016
K. pneumoniae Hospital sewage 1 Zhao, Feng, et al. 2016
E. coli Well water 2 Sun et al. 2017
2016 E. coli River and lake water 16 Zhou et al. 2017
Citrobacter freundii Lake water 2 Zhou et al. 2017
K. oxytoca Lake water 2 Zhou et al. 2017
Citrobacter braakii Lake water 2 Zhou et al. 2017
Enterobacter cloacae River water 1 Zhou et al. 2017
Germany 2012 S. enterica Paratyphi B mcr-5 NA 2 Borowiak, Fischer, et al. 2017
Malaysia 2014 E. coli Pond water 1 Petrillo et al. 2016
Norway 2010 E. coli Sea water 2 Jørgensen et al. 2017
Spain 2013 E. coli Sewage water 29 Ovejero et al. 2017
K. pneumoniae Sewage water 1 Ovejero et al. 2017
Switzerland 2012 E. coli River water 1 Zurfuh et al. 2016
Thailand 2014 – 2015 E. coli Canal water 2 Runcharoen et al. 2017
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NA: not available; Isolates carried mcr-1 unless stated otherwise in superscript.

Figure 2.

Figure 2.

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Geographical distribution of mcr-carrying bacteria.

To the best of our knowledge, the presence of all mcr except mcr-6 has been detected in samples from China (Yang et al. 2018; Zhang, Chen, Wang, Butaye, et al. 2018; Zhang, Chen, Wang, Yassin, et al. 2018). Thus far, mcr-2 (Belgium and Spain), mcr-3 (Brazil, Denmark, France, Germany, Japan, Spain and Thailand), mcr-4 (Italy and Spain), mcr-5 (Colombia, Japan, Spain and Germany) and mcr-6 (The United Kingdom) have been sparsely detected (Borowiak, Fisher et al. 2017; Carattoli et al. 2017; Liu L et al. 2017; Roer et al. 2017; AbuOun et al. 2018; Eichhorn et al. 2018; Fukuda et al. 2018; García et al. 2018; Haenni et al. 2018; Hammerl et al. 2018; Hernández et al. 2017; Kieffer et al. 2018; Litrup et al. 2017; Wang et al. 2018; Wise et al. 2018; Xavier et al. 2016; Yamaguchi et al. 2018; Yang et al. 2018).

The identification of mcr in sea gulls and migratory penguins is an alarming event due to the possibility for rapid global dissemination, as these flight animals are capable to migrate intercontinentally (Liakopoulos et al. 2016; Ruzauskas and Vaskeviciute 2016; Sellera et al. 2016). Trading of food products such as livestock, meat and vegetables can potentially be another significant force driving the spread of mcr globally (Hasman et al. 2015; Doumith et al. 2016; Grami et al. 2016; Kluytmans-van den bergh et al. 2016; Veldman et al. 2016). In addition, the global trade of exotic animals (Unger et al. 2016) and human travelers may also play a key role in the dissemination of mcr worldwide (Arcilla et al. 2016; Doumith et al. 2016). Fortunately, complete elimination of mcr-carrying isolates from travelers after their return to home country signifies that a biological cost could be conferred by mcr in the absence of polymyxins as the selective pressure, and as such the spread could be mitigated by limiting the use of polymyxins (Arcilla et al. 2016).

Transmission of mcr

By far, livestock is regarded as the main reservoir for mcr due to the heavy usage of polymyxins for prophylaxis, metaphylaxis and therapeutic purposes as well as a growth promoter (Kempf et al. 2016; Liu YY et al. 2016; Nordmann and Poirel 2016). Among livestock, the highest prevalence was observed among poultry, mainly in China and Germany. Approximately one third of the total mcr-positive isolates from livestock were from pigs, mainly attributed by China and Japan. The transferability of the mcr-carrying plasmid from isolates of animal origin to humans was demonstrated by in vitro conjugation and transformation experiments, showing successful transfer of a mcr-1 plasmid (pHNSHP45) from pig into common human pathogenic Enterobacteriaceae and Pseudomonas aeruginosa (Liu YY et al. 2016). Bacteria carrying mcr (mcr-1) have also been identified from pets and the possibility of these bacteria infecting humans is another avenue towards the interspecies spread (Liakopoulos et al. 2016; Zhang XF et al. 2016). The zoonotic potential of mcr-carrying bacteria has been postulated by comparing the genetic determinants of the mcr-carrying isolates from animal and human sources (Elnahriry et al. 2016; Poirel, Kieffer, Liassine, et al. 2016; Poirel and Nordmann 2016). Besides, the widespread of mcr among livestocks/meat/food products and identification of mcr in the human microbiome (mcr-1) suggested the potential transmission via the food chain; however, more definite evidence is required to draw this conclusion (Hu Y et al. 2016). The isolation of a mcr-positive Enterobacteriaceae (mcr-1) from infants who had not started solid diet and had no history of contact with livestock, suggested other possible transmission routes besides food chain and zoonotic transfer (Gu et al. 2016; Zhang R et al. 2016). More worryingly, mcr was identified from water sources, including untreated river wastewater, wastewater treatment plants, seawater, lake, pond, canal and well. This could contribute to the rapid spreading of polymyxin resistance to animals and humans (Petrillo et al. 2016; Zurfuh et al. 2016; Fernandes et al. 2017; Hembach et al. 2017; Jørgensen et al. 2017; Marathe et al. 2017; Runcharoen et al. 2017; Sun et al. 2017).

Epidemiology of mcr in humans and potential clinical impact

The mcr-positive bacteria have been isolated from people of various ages ranging from new-born to elderly (Prim et al. 2016; Zheng et al. 2016). These include patients, elderly residents at long-term aged care facilities in Italy (Giufrè et al. 2016), European travelers who had visited South America, Africa and Asia countries (Arcilla et al. 2016; Bernasconi et al. 2016; Doumith et al. 2016), as well as pilgrims who had traveled to Mecca during Hajj (Leangapichart et al. 2016). The most worrying situation is the detection of mcr in asymptomatic patients (Hu Y et al. 2016; Olaitan et al. 2016; Ruppé et al. 2016), which might further contribute to the silent dissemination. The vast majority of mcr-positive isolates were recovered from fecal samples (cf. Supplementary information Table S3). The Gram-negative species carrying mcr isolated from patients diagnosed with gastrointestinal disorder include E. coli, K. pneumoniae and Salmonella enterica (Doumith et al. 2016; Gu et al. 2016; Ye et al. 2016). The presence of mcr in Shigella sonnei (mcr-1) has been reported only once from a child suffering from dysenteric diarrhea (Thanh et al. 2016). Findings of mcr-positive isolates in the human gut microbiome (mcr-1) of healthy individual is a matter of great concern as gut flora can act as a mixing vessel which facilitates mcr dissemination by horizontal gene transfer (Hu Y et al. 2016; Ruppé et al. 2016). The mcr-harboring bacterial species isolated from patient urine samples were mainly E. coli, and less frequently K. pneumoniae, Enterobacter cloacae and S. enterica (cf. Supplementary information Table S3). Another mcr-carrying Enterobacter species, Enterobacter aerogenes was reported twice from clinical patients in China (Zeng et al. 2016; Wang Y et al. 2017). It is worth noting that the mcr-positive bacterial species isolated from bloodstream were mainly E. coli, with the exception of a few reports on mcr-harboring S. enterica and K. pneumoniae (cf. Supplementary information Table S3). Fortunately, many clinical mcr-harboring isolates were still susceptible to a number of other antimicrobial agents such as carbapenem and tigecycline (Quan et al. 2017; Saavedra et al. 2017). It is debatable whether surveillance cultures should be conducted for mcr when strains are still susceptible to most of antibiotic classes. Nevertheless, the dissemination of mcr-mediated polymyxin resistance should not be dismissed, as plasmids can be easily mobilized to MDR Gram-negatives.

Microbiology

Impact of mcr on polymyxin susceptibility

Transformation and conjugation methods are frequently utilized to study the transferability of the mcr-carrying plasmids and the impact of its acquisition on the polymyxin MIC (cf. Table 2). Broth microdilution is well accepted as the best method for testing polymyxin susceptibility, while other methods (e.g. Etest and disk diffusion) are less reliable but still used in clinical microbiology laboratory worldwide (Poirel, Jayol, et al. 2017; Simar et al. 2017). Generally, an increase in the polymyxin MICs was observed as mcr-carrying plasmid was introduced into polymyxin-susceptible strains (cf. Table 2). The successful conjugation of most mcr-harboring plasmids into the recipient strains led to the formation of transconjugants with comparable polymyxin MICs (4 – 16 mg/L) as the respective mcr donor strains (cf. Table 2). Further increased in colistin resistance in originally resistant E. coli strains (2 mg/L to 8 mg/L; 8 mg/L to 32 mg/L) was observed when mcr-1 plasmid was introduced into these two strains with an existing chromosomal pmrB mutation which is known to confer polymyxin resistance (Jayol et al. 2017). The extent of polymyxin resistance was not affected by the co-existence of multiple mcr-harboring plasmids in a single isolate (Li R et al. 2017; Zurfluh et al. 2017). However, a study demonstrated higher colistin MICs (8 mg/L) in S. enterica carrying multiple copies of mcr-5-harboring plasmid, as compared to the isolates with only one copy of chromosomal mcr-5 (4 mg/L) (Borowiak, Fischer, et al. 2017). Although we know that mcr confers resistance to polymyxins, unexpectedly mcr (more specifically mcr-1) has also been detected in colistin-susceptible E. coli strains (colistin MICs of 0.125 and less than 0.06 mg/L) (Liassine et al. 2016; Quan et al. 2017). The mcr-1 in a susceptible strain was reactivated following exposure to polymyxin, leading to a polymyxin-resistant phenotype (Thanh et al. 2016). This brings about the possibility for silent dissemination of mcr and further reactivation of the gene following polymyxin exposure.

Table 2.

Polymyxin B and colistin MICs of mcr-carrying strains and their respective transformants and/or transconjugants.

Reference Bacterial strain Description mcr Polymyxin B Colistin
MIC (mg/L) MIC fold-change MIC (mg/L) MIC fold-change
Liu YY et al. 2016 E. coli SHP45 Original mcr-1 positive isolate from pig + 4 8
E. coli C600 Recipient − 0.5 8 0.5 16
E. coli C600 transconjugant of E. coli SHP45 Transconjugant + 4 8
E. coli E11 Recipient − 0.5 4 0.5 8
E. coli E11 + pHNSHP45 Transformant + 2 4
K. pneumoniae MPC11 Recipient − 0.5 8 0.5 16
K. pneumoniae MPC11 + pHNSHP45 Transformant + 4 8
K. pneumoniae 1202 Recipient − 0.5 8 0.5 8
K. pneumoniae 1202 + pHNSHP45 Transformant + 4 4
P. aeruginosa HE26 Recipient − 0.5 8 0.5 16
P. aeruginosa HE26 + pHNSHP45 Transformant + 4 8
E. coli W3110 + pUC18 Recipient (lab strain) − 0.5 4 0.5 4
E. coli W3110 + pUC18mcr-1 Transformant + 2 2
Gu et al. 2016 K. pneumoniae 15451–1 Original mcr-1 positive isolate from human + NA 16
E.coli C600 Recipient − NA NA ≤1 >16
E. coli C600 transconjugant of K. pneumoniae 15451–1 Transconjugant + NA 16
E. coli 15451–2 Original mcr-1 positive isolate from human + NA 16
E.coli C600 Recipient − NA NA ≤1 >16
E. coli C600 transconjugant of E. coli 15451–2 Transconjugant + NA 16
Yang YQ et al. 2016 S. enterica SC23 Original mcr-1 positive isolate from chicken + 8 8
E. coli J53 Recipient − <0.25 >32 <0.25 >32
E. coli J53 transconjugant of S. enterica SC23 Transconjugant + 8 8
Zeng et al. 2016 Enterobacter aerogenes GB68 Original mcr-1 positive isolate from human + 16 16
E.coli C600 Recipient − <0.25 >64 <0.25 >64
E.coli C600 transconjugant of Enterobacter aerogenes GB68 Transconjugant + 16 16
Enterobacter cloacae GB38 Original mcr-1 positive isolate from human + >32 >32
E.coli C600 Recipient − <0.25 >64 <0.25 >64
E.coli C600 transconjugant of Enterobacter cloacae GB38 Transconjugant + 16 16
Sonnevend et al. 2016 E. coli BA76 Original mcr-1 positive isolate from human + NA 16
E. coli J53RAZ Recipient − NA NA 0.25 16
E. coli J53RAZ transconjugant of E. coli BA76 Transconjugant + NA 4
E. coli BA77 Original mcr-1 positive isolate from human + NA 16
E. coli J53RAZ Recipient − NA NA 0.25 16
E. coli J53RAZ transconjugant of E. coli BA77 Transconjugant + NA 4
E. coli SA26 Original mcr-1 positive isolate from human + NA 16
E. coli J53RAZ Recipient − NA NA 0.25 16
E. coli J53RAZ transconjugant of E. coli SA26 Transconjugant + NA 4
E. coli ABC149 Original mcr-1 positive isolate from human + NA 16
E. coli DH5α Recipient − NA NA 0.25 32
E. coli DH5α + pABC149 Transformant + NA 8
Berrazeg et al. 2016 E. coli SE65 Original mcr-1 positive isolate from human + NA 4
E. coli J53 Recipient − NA NA 0.125 32
E. coli J53 transconjugant of E. coli SE65 Transconjugant + NA 4
Li XP et al. 2016 S. enterica GDS78, GDS79, GDS82, GDS141 Original mcr-1 positive isolate from animal + NA 16
E. coli C600 Recipient − NA NA 0.125 32
E. coli C600 T(GDS78T, GDS79T, GDS82T, GDS141T) Transconjugant + NA 4
Zheng et al. 2016 E. coli 1002 Original mcr-1 positive isolate from human + 4 4
E. coli J53 Recipient − 0.25 8 0.5 8
E. coli J53 transconjugant of E. coli 1002 Transconjugant + 2 4
E. coli 2474 Original mcr-1 positive isolate from human + 4 4
E. coli J53 Recipient − 0.25 16 0.5 8
E. coli J53 transconjugant of E. coli 2474 Transconjugant + 4 4
Zhong et al. 2016 E. coli GB049 Original mcr-1 positive isolate form human + 16 8
E.coli EC600 Recipient − 0.5 32 0.25 64
E.coli EC600 transconjugant of E. coli GB049 Transconjugant + 16 16
E. coli GB090 Original mcr-1 positive isolate form human + 16 16
E.coli EC600 Recipient − 0.5 32 0.25 64
E.coli EC600 transconjugant of E. coli GB090 Transconjugant + 16 16
Liu BT et al. 2016 E. coli WF5–19 Original mcr-1 positive isolate from chicken + NA 4
E. coli C600 Recipient − NA NA 0.25 16
E. coli C600 transconjugant of E. coli WF5–19 Transconjugant + NA 4
Cronobacter sakazakii WF5–19C Original mcr-1 positive isolate from chicken + NA 4
E. coli C600 Recipient − NA NA 0.25 16
E. coli C600 transconjugant of Cronobacter sakazakii WF5–19C Transconjugant + NA 4
Cronobacter sakazakii WF5–21C Original mcr-1 positive isolate from chicken + NA 4
E. coli C600 Recipient − NA NA 0.25 16
E. coli C600 transconjugant of Cronobacter sakazakii WF5–21C Transconjugant + NA 4
Ortiz de la Tabla et al. 2016 E. coli (unnamed) Original mcr-1 positive isolate from human + NA 4
E. coli Hb101 Recipient − NA NA 0.5 8
E. coli Hb101 transconjugant of E. coli (unnamed) Transconjugant + NA 4
Lu et al. 2017 S. enterica Typhimurium YL14P053 Original mcr-1.6 positive isolate from human + NA 4
S. enterica Typhi CT18 Recipient − NA NA 0.125 32
S. enterica Typhi CT18 transconjugant of S. enterica Typhimurium YL14P053 Transconjugant + NA 4
E. coli J53 AziR Recipient − NA NA 0.125 32
E. coli J53 AziR transconjugant of S. enterica Typhimurium YL14P053 Transconjugant + NA 4
K. pneumoniae BJ1988 Recipient − NA NA 0.125 32
K. pneumoniae BJ1988 transconjugant of S. enterica Typhimurium YL14P053 Transconjugant + NA 4
Conceição-Neto et al. 2017 E. coli CCBH20178 Original mcr-1 positive isolate from human + NA 8
E. coli J53 Recipient − NA NA <0.125 >32
E. coli J53 transconjugant of E. coli CCBH20178 Transconjugant + NA 4
E. coli CCBH20607 Original mcr-1 positive isolate from human + NA 8
E. coli J53 Recipient − NA NA <0.125 >32
E. coli J53 transconjugant of E. coli CCBH20607 Transconjugant + NA 4
E. coli CCBH20180 Original mcr-1 positive isolate from human + NA 4
E. coli J53 Recipient − NA NA <0.125 >64
E. coli J53 transconjugant of E. coli CCBH20180 Transconjugant + NA 8
Aires et al. 2017 K. pneumoniae CCBH24080 Original mcr-1 positive isolate from human + NA 16
E. coli J53 Recipient − NA NA <0.125 >64
E. coli J53 transconjugant of K. pneumoniae CCBH24080 Transconjugant + NA 8
Kim et al. 2017 E. coli 28 Original mcr-1 positive isolate from human + NA 8
E. coli J53 Recipient − NA NA 0.5 16
E. coli J53 transconjugant of E. coli 28 Transconjugant + NA 8
Yin et al. 2017 E. coli WJ1 Original mcr-3 positive isolate from porcine + NA 8
E. coli C600 Recipient − NA NA 0.5 8
E. coli C600 transconjugant of E. coli WJ1 Transconjugant + NA 4
Liu L et al. 2017 E. coli WCHECLL123 Original mcr-3.5 and mcr-1 positive isolate from human + NA 8
E. coli J53 Recipient − NA NA 1 4
E. coli J53 transconjugant of E. coli WCHECLL123 (mcr-1) Transconjugant + NA 4
E. coli J53 transconjugant of E. coli WCHECLL123 (mcr-3.5) Transconjugant + NA NA 4 4
Carattoli et al. 2017 S. enterica Typhimurium R3445 Original mcr-4 positive isolate from pig + NA 8
E. coli DH5α Recipient − NA NA 0.25 8
E. coli DH5α + pMCR_R3445 Transformant + NA 2
E. coli R4287 Original mcr-4 positive isolate from pig + NA 8
E. coli CSH26 RifR Recipient − NA NA 0.25 16
E. coli CSH26 RifR transconjugant of E. coli R4287 Transconjugant + NA 4
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NA: not available; Original mcr-positive isolates are highlighted in grey.

Prevalence of mcr in Gram-negative species

E. coli is the most prevalent species among the mcr-positive isolates reported so far, accounting for approximately 91% of the total mcr-carrying isolates, followed by S. enterica (~7%) and K. pneumoniae (~2%). It is noteworthy that the total number of S. enterica screened for mcr was at least 12-fold greater than K. pneumoniae. This is likely due to the fact that S. enterica is one of the major food-borne pathogens and mcr is very likely to be disseminated via food chain (Zurfluh et al. 2017). The mcr has been detected on very rare occasion in Klebsiella oxytoca, Citrobacter freundii, Citrobacter braakii, Cronobacter sakazakii, Kluyvera ascorbata, Shigella sonnei, Raoultella ornithinolytica, Proteus mirabilis, Moraxella, Aeromonas and Enterobacter species with a total prevalence rate of approximately 0.2%. Among the bacterial species which have been tested, mcr has not been detected in wild-type isolates of Klebsiella ozaenae, Morganella morganii, Providencia rettgeri, Pseudomonas aeruginosa, Campylobacter, Serratia and Acinetobacter species. Although mcr has yet to be found in wildtype Pseudomonas and Acinetobacter species, it has been demonstrated that, after mcr-1 was introduced into Acinetobacter baumannii and Pseudomonas aeruginosa, their lipid A was modified by pEtN; interestingly, greater colistin resistance was observed in Acinetobacter baumannii (64- to >128-fold increase in colistin MICs) as compared to only modest changes in colistin susceptibility in Pseudomonas aeruginosa (2- to 4-fold increase in colistin MICs) (Liu YY et al. 2017). Overall, the true prevalence of mcr has yet to be fully understood due to the limits of many studies which only screened for the presence of mcr in extended-spectrum-β-lactamase (ESBL)-producing isolates and polymyxin-resistant isolates. Such limitations could lead to the underestimation of the true prevalence for mcr isolates.

Co-occurrence with β-lactamases and carbapenemases

Carbapenem is often the treatment option for ESBL-associated bacterial infection and unfortunately increasing emergence of carbapenemase-producing bacteria has been reported (Meletis 2016; Thomson 2010). This situation has brought back polymyxins as a last-resort against carbapenemase-producing MDR Gram-negative bacteria (Trecarichi and Tumbarello 2017). Hence, the co-occurrence of mcr with carbapenemases may herald the rise of a post-antibiotic era. The mcr was found to be frequently associated with β-lactamase-producing Enterobacteriaceae carrying blaCTX-M and blaTEM of various variants as well as carbapenem-resistant Enterobacteriaceae harboring blaOXA-48, blaOXA-181, blaKPC-2, blaKPC-3, blaNDM-1, blaNDM-4, blaNDM-5 and blaNDM-9 (cf. Supplementary information Table S4). Importantly, the discovery of β-lactamase and carbapenemase genes co-localizing with mcr on the same conjugative plasmid is the most worrisome, as Gram-negative pathogens can acquire both types of antibiotic resistance genes via horizontal transmission. The co-localization of the β-lactamase and carbapenemase genes (blaTEM-1, blaCTX-M-1, blaCTX-M-55, blaNDM-5) with mcr most commonly occurs on the IncHI2 (Grami et al. 2016; Sonnevend et al. 2016; Zurfluh, Klumpp, et al. 2016; Yi et al. 2017) and IncI2 (Sonnevend et al. 2016; Yang YQ et al. 2016; Yi et al. 2017) plasmids, and less commonly on IncFI (Zeng et al. 2016; Zhong et al. 2016), IncK2 (Donà, Bernasconi, Pires, et al. 2017) and IncX3-IncX4 hybrid plasmids (Sun et al. 2016).

Potential origins of mcr

Thus far, mcr-1 to -7 have been reported. MCR-1 and MCR-2 share the highest percentage of amino acid sequence identity (81%), are believed to be originated from Moraxella species, common animal pathogens. MCR-1 and MCR-2 share 59 – 64% amino acid similarities with those found in M. porci, M. osloensis, M. lincolnii and M. catarrhalis (Kieffer et al. 2017). MCR-3 and MCR-7, which share 70% amino acid similarity, might be of Aeromonas origin (Yang et al. 2018; Yin et al. 2017). MCR-4, sharing only 34% amino acid sequence identity with MCR-1 might have been originated from Shewanella frigidimarina (Carattoli et al. 2017). MCR-5 has distinct amino acid sequences from the all the others (34 – 37% similarities) and its origin is still unknown (Borowiak, Fischer, et al. 2017). The heavy usage of colistin in animals is very likely a major selective factor facilitating the mobilization of these mcr genes from natural source to Enterobacteriaceae.

Genetic organization of mcr-harboring plasmids

The detection of mcr on different classes of plasmids indicated a high diversity of mcr plasmid reservoirs (cf. Table 3). Numerous studies have confirmed mcr on three major types of plasmids: IncI2, IncHI2 and IncX4. There are also several other types of plasmids carrying mcr, including IncHI1, IncF, IncFI, IncFIB, IncFII, IncP, IncP-1, IncK2 and phage-like IncY (cf. Supplementary information Table S5). To date, only mcr-4 and mcr-5 have been identified on small ColE-type plasmid (Borowiak, Fischer, et al. 2017; Carattoli et al. 2017). Of all the different plasmid reservoirs, the IncHI2-type plasmids are often associated with various antimicrobials resistance (cf. Figure 3). As compared to IncI2 and IncHI2-type plasmids, the genetic contexts are more conserved in IncX4-type plasmids except pICBEC7Pmcr which has an additional IS1294 resulting in truncated mobA (Sellera et al. 2016) (cf. Figure 3). Although mcr was initially reported as a plasmid-mediated polymyxin resistance gene, mcr-1 has been identified in the chromosome of E. coli strains and mcr-5 was identified in the chromosome of a S. enterica (cf. Supplementary information Table S5). The presence of ISApl1-mcr-1 region in the chromosome postulates the importance of ISApl1 for the chromosomal integration of mcr-1 and represents another transmissibility factor for the vertical transmission. Remarkably, a triplicated ISApl1-mcr-1-Δpap in a tandem arrangement in the chromosome was described in an E. coli isolated from humans, indicating a more diverse genetic context of mcr (Yu, Ang, Chong, et al. 2016).

Table 3.

Characterization of mcr-harboring plasmids with complete sequences in Genbank.

Year Country Source Species Plasmid Type Length (bp) ISApI1 Accession number
2011 – 2012 Belgium Pig E. coli pKP37-BE IncX4 35,104 − LT598652
2012 Switzerland River water E. coli pOW3E1 IncX4 34,640 − KX129783
2013 Estonia Pig E. coli pESTMCR IncX4 33,311 − KU743383
2013 Brazil Magellanic penguin E. coli pICBEC7Pmcr IncX4 34,992 − CP017246
2014 China Pig E. coli pECGD-8–33 IncX4 33,307 − KX254343
2014 Italy Human K. pneumoniae pMCR1.2-IT mcr-1.2 IncX4 33,303 − KX236309
2014 The United States Human E. coli pMCR1-NJ-IncX4 IncX4 33,395 − KX447768
2015 China Human K. pneumoniae pmcr1_IncX4 IncX4 33,287 − KU761327
2015 China Human E. coli pE15004 IncX4 33,309 − KX772777
2015 China Pig E. coli pECJS-B65–33 IncX4 33,298 − KX084392
2015 China Sewage E. coli pMCR_WCHEC1618 mcr-1.4 IncX4 33,309 − KY463454
2015 Portugal Pig E. coli pLV23529-MCR-1.9 mcr-1.9 IncX4 33,303 − KY964067
2015 South Africa Human E. coli pAF48 IncX4 31,808 − KX032520
2016 Brazil Human E. coli pICBEC72Hmcr IncX4 33,304 − CP015977
2011 Australia Human E. coli pJIE2288–1 IncI2 60,733 − KY795977
2013 Australia Human E. coli pJIE3685–1 IncI2 60,960 − KP795978
2013 Malaysia Chicken E. coli pEC5–1 IncI2 61,735 − CP016185
2013 Malaysia Pond water E. coli pEC13–1 IncI2 60,218 − CP016186
2013 Malaysia Chicken E. coli pS2.14–2 IncI2 60,950 − CP016187
2013 China Chicken E. coli pHeN867 mcr-1.3 IncI2 60,757 − KU934208
2014 China Chicken K. pneumoniae pSC20141012 mcr-7 IncI2 65,631 − MG267386
2015 Bahrain Human E. coli pBA76-MCR-1 IncI2 64,942 − KX013540
2015 Bahrain Human E. coli pBA77-MCR-1 IncI2 62,661 − KX013539
2015 China Human E. coli pmcr1_IncI2 IncI2 64,964 − KU761326
2015 China Pig E. coli pECJS-61–63 IncI2 63,656 − KX084393
2015 China Hospital sewage Kluyvera ascorbata pMCR_1410 IncI2 57,059 − KU922754
2015 China Human E. coli pE15017_00 IncI2 65,375 − KX772778
2016 The United States Pig E. coli pSLy1 IncI2 65,888 − CP015913
2016 The United States Pig E. coli pSLy21 IncI2 63,329 − CP016405
2013 – 2015 Argentina Human E. coli pMCR-M15049 mcr-1.5 IncI2 61,198 + KY471308
2013 – 2015 Argentina Human E. coli pMCR-M17059 mcr-1.5 IncI2 61,531 + KY471310
2013 – 2015 Argentina Human E. coli pMCR-M19241 mcr-1.5 IncI2 61,584 + KP471311
2012 China Chicken E. coli pA31–12 IncI2 67,134 + KX034083
2013 China Pig E. coli pHNSHP45 IncI2 64,015 + KP347127
2013 United Arab Emirates Human E. coli pABC149-MCR-1 IncI2 61,228 + KX013538
2014 China Chicken S. enterica pSCS23 IncI2 65,419 + KU934209
2014 South Africa Human E. coli pAf23 IncI2 61,177 + KX032519
2015 China Chicken Cronobacter sakazakii pWF-5–19C_mcr-1 IncI2 65,203 + KX505142
2015 China Sewage E. coli pMCR_WCHEC1604-IncI2 mcr-1.7 IncI2 62,098 + KY829117
2015 South Africa Chicken E. coli pVT553 IncI2 62,219 + KU870627
2011 – 2012 Belgium Cattle E. coli pKH457–3-BE IncP 79,798 − KU353730
2014 China Human S. enterica Typhimurium pMCR16_P053 mcr-1.6 IncP 47,824 − KY352406
2015 China Hospital sewage K. pneumoniae pMCR_1511 IncP 57,278 + KX377410
2017 China Human E. coli pMCR3_LL123 mcr-3.5 IncP 52,208 − MF489760
2011 – 2012 Belgium Pig E. coli pKP81-BE IncFII 91,041 + KU994859
2016 The United States Human E. coli pMR0516mcr IncF 225,069 + KX276657
2014 Switzerland Vegetables (imported from Thailand) E. coli pH226B IncHI1 209,401 − KX129784
2013 Malaysia Chicken E. coli pEC2_1–4 IncHI1 230,278 + CP016183
2013 Malaysia Pig E. coli pEC2–4 IncHI1 235,403 + CP016184
2008 Germany Chicken S. enterica Paratyphi B pSE08-00436-1 IncHI2 264,914 + CP020493
2012 Saudi Arabia Human E. coli pSA26-MCR-1 IncHI2 240,367 + KU743384
2013 China Pig E. coli pHNSHP45–2 IncHI2 251,493 + KU341381
2015 China Pig E. coli pECJS-59–244 IncHI2 243,572 + KX084394
2015 China Pig E. coli pECJS-B60–267 IncHI2 267,486 + KX254341
2015 Switzerland Chicken meat (imported from Italy) E. coli pS38 IncHI2 247,885 + KX129782
2015 China Pig E. coli pWJ1 mcr-3 IncHI2 261,119 − KY924928
2015 China Pig E. coli pHYEC7-mcr1 IncY 97,559 + KX518745
2016 China Pig E. coli pMCR-1-P3 IncY 97,386 + KX880944
2012 Germany Poultry S. enterica Paratyphi B pSE12–02541 mcr-5 ColE 17,156 − KY807920
2013 Germany Chicken meat S. enterica Paratyphi B pSE13-SA01718 mcr-5 ColE 12,201 − KY807921
2013 Italy Pig S. enterica Typhimurium pMCR_R3445 mcr-4 ColE10 8,749 − MF543359
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Plasmids carried mcr-1 unless stated otherwise in superscript.

Figure 3.

Figure 3.

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Comparison of the genetic context of mcr-1 harboring (A) IncI2 plasmids with pHNSHP45 as the reference sequence; (B) IncHI2 plasmids with pHNSHP45–2 as the reference sequence; (C) IncX4 plasmids with pICBEC7Pmcr as the reference sequence, using BRIG (Alikhan et al. 2011). The mcr-1 and ISApl1 transposase are illustrated in red, whereas other antimicrobial resistance genes are illustrated in purple at the outermost circle containing the CDS annotations.

It has been demonstrated that the transposon Tn6330 element (ISApl1-mcr-1-orf-ISApl1) could be excised from the plasmid, forming a circular intermediate of ISApl1-mcr-1-orf, which might be integrated into other ISApl1-carrying plasmids (Li R et al. 2016). The mobilization of mcr-1 by ISApl1-mediated transposition was demonstrated in vitro (Poirel, Kieffer and Nordmann 2017). Plasmid analysis from various studies revealed that the ISApl1 family transposase does not always co-present with mcr in the plasmid. ISApl1 is usually present in IncHI2-type plasmids (~200 kb), can be either present or absent in IncI2-type plasmids (~60 kb), and completely absent in IncX4-type plasmids (~30 kb) (cf. Figure 3). A possible explanation for this observation is that mcr may have originated from plasmid and their co-evolution occurred via acquisition of ISApl1, leading to rapid mobilization onto other plasmids (Kuo et al. 2016; Petrillo et al. 2016). Another possibility is that ISApl1 transposase is lost after translocation of the ISApl1-mcr-1 element into the plasmid with the purpose to strengthen the stability of mcr per se in the plasmid (Li A et al. 2016; Snesrud et al. 2016). The mcr-3 was found to be associated with TnAs2 (Yin et al. 2017) and TnAs3 (Liu L et al. 2017), which are the Tn3-family transposon and were found only in Aeromonas salmonicida. This fortifies the possible transfer of mcr-3 from Aeromonas species to Enterobacteriaceae. The mcr-5 gene was found to be located on a Tn3-family transposon which has been identified in Cupriavidus gilardii (Borowiak, Fischer, et al. 2017).

The transferability of mcr-carrying plasmids between bacteria depends on the conjugative properties of the plasmid backbone. The defective conjugation potential can be due to the disrupted or lacking of tra region (encodes for conjugal transfer protein) (Bernasconi et al. 2016; Cui et al. 2017). The mcr-1 carrying plasmid, pMCR_1410 from Kluyvera ascorbata was found to possess the ability to transfer between different Gram-negative species, unlike the first mcr-1-harboring plasmid identified, pHNSHP45. Comparison of pMCR_1410 and pHNSHP45 revealed that the absence of traC in pHNSHP45 could cause its inability for interspecies conjugation, suggested that traC gene could possibly be responsible for interspecies transfer of the plasmid (Zhao and Zong 2016). This finding is alarming due to the potential for the spread of mcr to a more diverse bacterial species pool, which highlights the need for further investigations into the genes involved in the conjugative transfer of mcr.

Future perspective

Since the discovery of mcr, the number of mcr-harboring isolates has been increasingly reported worldwide at an alarming rate. Notwithstanding, the prevalence of mcr remains much higher in livestock as compared to humans, which is in line with its purported agricultural origins. Luckily, the use of colistin has been recently banned for agriculture purposes in China and Brazil (Walsh and Wu 2016; Monte et al. 2017). The increasing usage of polymyxins clinically may increase the potential for wide dissemination of mcr in the nosocomial setting. As polymyxins are the last therapeutic option for life-threatening infections caused by Gram-negative ‘superbugs’, every effort must be made to minimize the emergence of resistance, in particular due to mcr.

Supplementary Material

Supp1

Acknowledgments

Disclosure statement

J.L. and T.V. are supported by grants from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (R01 AI111965 and AI132154). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health. J.L. is an Australian National Health and Medical Research Council (NHMRC) Senior Research Fellow. T.V. is an Australian NHMRC Career Development Research Fellow.

Footnotes

Declaration of interest

The authors report no declarations of interest.

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