2 Polymyxin Resistance: Complex

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Transferability of MCR-1/2 Polymyxin Resistance: Complex Dissemination and Genetic Mechanism Youjun Feng ACS Infect. Dis., Just Accepted Manuscript • DOI: 10.1021/acsinfecdis.7b00201 • Publication Date (Web): 03 Feb 2018 Downloaded from http://pubs.acs.org on February 4, 2018

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ACS Infectious Diseases

Transferability of MCR-1/2 Polymyxin Resistance: Complex Dissemination and Genetic Mechanism

Youjun Feng1,2*

1

Department of Medical Microbiology & Parasitology, Zhejiang University School of

Medicine, Hangzhou 310058, China 2

College of Animal Sciences, Zhejiang University, Hangzhou 310058, China

*To whom correspondence should be addressed: [email protected] Tel: 86-571-88208524; Fax: 86-571-88208524

1

ACS Paragon Plus Environment

ACS Infectious Diseases 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Polymyxins, a group of cationic antimicrobial polypeptides, act as a last-resort defense against lethal infections by carbapenem-resistant Gram-negative pathogens. Recent emergence and fast spread of mobilized colistin resistance determinant mcr-1 argues the renewed interest of colistin in clinical therapies, threatening global public health and agriculture production. This mini-review aims to present an updated overview on mcr-1, covering its global dissemination, the diversity of its hosts/plasmid reservoirs, the complexity in the genetic environment adjacent to mcr-1, the appearance of new mcr-like genes and the molecular mechanisms for MCR-1/2 colistin resistance.

Key words: Colistin resistance, MCR-1, mcr-like genes, Global dissemination, Plasmid reservoir

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Clinical Use of Carbapenem and Colistin The clinical choice between antibiotics is often a trade-off between the effectiveness of the drug and the potential to develop antibiotic resistance. The overuse/abuse of anti-microbials, in both agricultural and clinical setting, is leading to the rapid development of novel multi-drug resistances (MDR) in pathogens. These MDR organisms cause lethal infections leading to more than 700,000 deaths each year1, 2. Among them, Acinetobacter baumannii (A. baumannii) is a notorious agent of healthcare-associated infections, which has evolved different mechanisms to gain an intrinsic antibiotic resistance, rendering most of β-lactam antibiotics ineffective. It seems true that carbapenems are one of the few clinical options available in the treatment of infections by the MDR-Enterobacteriaceae. However, the emergence and global distribution of carbapenemase-producing Enterobacteriaceae (CPE), referred to as “nightmare bacteria”, has challenged the use of carbapenems in clinical therapy 3. The CPE includes Klebsiella pneumoniae (K. pneumoniae) 4, 5, E. coli 6, Enterobacter cloacae 7, 8, etc. Indeed, lethal infections by such CPE bugs kill up to half of patients through bloodstream infections. Therefore, it seems likely that carbapenem resistance in CPE is an increasingly-devastating clinical problem, whose genetic determinants involve K. pneumoniae carbapenemase (KPC) 4, 5, New Delhi Metallo-β-lactamase (NDM) 3, 9, 10 and Verona Integron-Mediated Metallo-β-lactamase (VIM) 10, 11.

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Polymyxins are a group of cyclic peptide antimicrobials (with five subtypes: polymyxin A, B, C, D & E) that are naturally produced by Paenibacillus polymyxa 12. Historically, the action mode of polymyxins, like polymyxin B (Fig. 1A) and colistin (polymyxin E, Fig. 1B), is believed to be the disruption of bacterial membrane integrity and permeability upon binding of these cationic antibiotics to the initial target, the negatively-charged lipid A moieties of lipopolysaccharides (LPS-lipid A) of the bacterial outer membrane 13. Although it possesses neuro-toxicity and renal toxicity to some extent, colistin is still regarded as an alternative “last-resort” approach to combat CRE infections 14. Unfortunately, this renewed interest in colistin as a clinical therapeutic has been dampened by the discovery 1 and rapid spread 1, 15, 16

of mobilized colistin resistance (MCR-1) transferred by various plasmids amongst

diversified species of Enterobacteriaceae.

Transmission of mcr-1 within Multiple Ecosystems Since its first detection in Southern China in late 2015 1, mcr-1 has been detected in almost 40 countries/regions across 5 of 7 continents worldwide 15, 17. The geographic distribution of mcr-1 (the genetic determinant of colistin resistance) involves developed countries like the United States of America 18-20, Japan 21, Italy 22, 23

and developing countries such as China 1, 16, Vietnam 24, 25, Laos 26 amongst others.

In total, over 11 species of Enterobacteriaceae have been found to carry mcr-1, including E. coli 27, K. pneumoniae 28, Salmonella enterica 29, Shigella sonnei 30, Enterobacter aerogenes 31, Enterobacter cloacae 31, Cronobacter sakazakii 32, 4


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Kluyvera ascorbata 33, Citrobacter freundii 34, Citrobacter braakii 35 and Raoultella ornithinolytica 36. Interestingly, tens of different sequence types have been assigned to mcr-1-bearing E. coli isolates 1, 15, 37, 38. From the view of ecological distribution, the carriage of plasmid-borne mcr-1 exhibits unprecedented complexity and diversity. So far, the list of reservoirs (host and/or vectors) where the mcr-1-carring bacteria grow/inhabit, is already quite long, at least include environments (rivers 39, 40, public beaches 41, well water 42, wastewater 43, 44 and hospital sewage 28, 33), foods (vegetables 36, 39 and meats 45-49), animals (wild birds 50, 51, housefly/blowfly 52, cattle 21, 48

, pigs 53, 54, poultry 47, 51, 55 and companion animals 56) and humans (inpatients 16, 19,

37, 57-59

& healthy individuals) 60-62. Though an increasing amount of data suggests that

flies may act as intermediate vectors for mcr-1 between companion animals and humans, the precise route for circulation/spread of mcr-1 remains largely mysterious.

Emergence of mcr-like Genes The transferability of colistin resistance seems to be largely mediated by diversified MCR-like intramembrane enzymes (Table 1 and Fig. 2). As of this mini-review, four additional mcr-like genes have been identified, namely mcr-2 63, mcr-3 64, mcr-4 65 and mcr-5 66 (Fig. 2B-E). In comparison to the representative MCR-1 [Acc. no.: ANH55937] 1, eleven functional genetic variants have been reported (Table 1), which include MCR-1.2 [Acc. no.: WP_065274078, Q3L] 67, MCR-1.3 [Acc. no.: WP_077064885, I37L] 68, MCR-1.4 [Acc. no.: WP_076611062, D440N], MCR-1.5 [Acc. no.: ARX60875, H452Y] 69, MCR-1.6 [Acc. no.: 5



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WP_077248208, R536H] 61, MCR-1.7 [Acc. no.: WP_085562392, A215T], MCR-1.8 [Acc. no.: NG_054697, Q3R], MCR-1.9 [Acc. no.: KY964067,

V413A], MCR-1.10

[Acc. no.: MF176238, M2V, R11C, A23S, M155V, M234T, A354T & A443T], MCR-1.11 [Acc. no.: NG_055784, with an additional residue of V8] and MCR-1.12 [Acc. no.: LC337668, Q3H]. Of note, three of them display a point mutation at the same position (Q3L in MCR1.2, Q3R in MCR-1.8 and Q3H in MCR-1.12). Thus, it seems that mcr-1 is evolving under an unknown selection pressure. Analyzing the global distribution of mcr-1 shows that MCR-1 (541 aa) is a prevalent member of MCR enzymes while MCR-2 (538 aa), a homologue of MCR-1 with 81% identity, is a rare member that has only been observed so far in an IncX4 plasmid from an E. coli isolate from Belgium 63. Both MCR-1 and MCR-2 are found in the same subclade in terms of the phylogeny of phosphoethanolamine (PEA)-lipid A transferases. Intriguingly, Moraxella species have been suggested to be reservoir hosts for MCR-1/2 since genetic homologues have been detected in their chromosome 70, 71. The candidate progenitors of MCR-1/2 include i) AXE82_07515 of M. osloensis [Acc. no.: AME01623, 548 aa] for MCR-1 71 and ii) two MCR-2 variants, MCR-2.1 of M. pluranimalium [Acc. no.: ASK49941, 538 aa] plus MCR-2.2 of Moraxella sp. MSG47-C17 [Acc. no.: ASK49942, 538 aa] 70.

Very recently, the third mcr-like gene, mcr-3 was revealed by Wang and coworkers 64 from an IncHI2-type plasmid pWJ1, from a swine isolate of E. coli in Shandong Province, China. Sequence alignment suggests that MCR-3 (541 aa) 6


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exhibits an appreciably higher similarity to the chromosome-encoded EptA (53.1%) than to MCR-1 (44.1%). This is consistent with the fact that MCR-3 is clustered in a sub-clade distinct from that of MCR-1 (or MCR-2). Similarly, ten genetic variants have also been assigned to MCR-3. Among them, MCR-3.6, MCR-8, MCR-9 and MCR-10 have a number of mutations (Table 1). The remaining six variants correspond to MCR-3.2 [Acc. no.: NZ_FLWO01000034, D295E] 64, MCR-3.3 [Acc. no.: NG_055492, G373V] 64, MCR-3.4 [Acc. no.: NG_055497, M23V], MCR-3.5 [Acc. no.: ERR1971735, T488I] 72 , MCR-3.7 [Acc. no.: MF489760, M23V, A457E & T488I] 73, and MCR-3.11 [Acc. no.: NG_056184, Q468T], respectively. Apart from the fact that MCR-3.6 contains three point-mutations 73, all the other five MCR-3 variants consistently possess a single residue substitution 73, 74. Since MCR-3 is a relatively weak version of MCR-like enzymes (i.e., the MIC of colistin is 2 µg/ml for MCR-3, whereas 4 µg/ml for MCR-1), the coexistence of MCR-1 and MCR-3 does not exhibit a significantly additive impact on polymyxin resistance 75. More intriguingly, two more novel MCR-like enzymes were elucidated from Salmonella species of animal origin in Europe i.e. MCR-4 [Acc. no.: MF543359, 541 aa] from Italy 65 and MCR-5 [Acc. no.: KY807920, 547 aa] from Germany 66. In particular, two more variants of MCR-4 have been detected, namely MCR-4.2 (Acc. no.: MG581979, Q331R) and MCR-4.3 (Acc. no.: MG026621, V179G, V236F). Unlike the scenario observed with MCR-1/2 and MCR-3, the discovery of MCR-4 65 and MCR-5 66 represents two additional unique members of the MCR-like enzyme collection and extends the diversity of MCR-aided transfer of colistin resistance. 7



Diversity in mcr-1-bearing Plasmid Reservoirs Following the initial description of an IncI2 plasmid pHNSHP45 carrying mcr-1, our earlier genetic studies have proposed the presence of diversity amongst mcr-1-harbouring plasmids (Fig. 2A) 1, 16, 53, 54. As expected, the mcr-1 gene was detected in the IncHI2 48, 51, 76, IncX4 77 and IncP 28, 61 plasmids 78, 79. As of the 15th of October, 2017, no less than 12 types of mcr-1-bearing plasmids have been determined 15

. Overall, the diversified replicon types are grouped into IncI2 1, IncHI2 76, IncP 28,

IncX4 76, 80, IncY 81, IncF 18, IncFI 31, IncFII 82, IncFIB 83, IncK2 84 including hybrid versions like IncX3-IncX4 85 and IncI2-IncFIB 15. Additionally, we observe that two types of distinct mcr-1-harboring plasmids (IncI2-type plasmid pGD65-3 & IncX4-like plasmid pGD65-4) can co-occur in a single E. coli isolate with phenotypic resistance to colistin 15. Most interestingly, the mcr-1 gene also appears in the MDR-containing bacteria with either ESBL 86, 87 or NDM-1 88 [or its variants NDM-5 89

& NDM-9 90], highlighting the possible emergence of super-bugs with pan-drug

resistance. This would most likely render the two-remaining line of refuge antibiotics [carbapenem and colistin] useless in the clinical therapeutics, implying that we are almost on cusp of a “post-antibiotic era”.

In addition, many other types of plasmids like IncP 91 were identified to harbor mcr-like genes (Fig. 2B-E), suggesting that the mcr-1-like genes might have been circulated by multiple plasmids in Enterobacteriaceae worldwide. However, the types 8


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of plasmids carrying other mcr-like genes are very few, due to the low prevalence rate of these mcr-like genes. As for mcr-2 gene, it is only found in an IncX4 plasmid 63, whereas the mcr-3 gene can be detected in IncHI2 plasmids 92, 93, as well as the IncP plasmid 94. Unexpectedly, we notice that the two genes mcr-4 and mcr-5 are transferred by the same ColE-type plasmid with relatively-small size 95, 96.

Complexity of Genetic Environment for mcr-like Genes The diversity of mcr-1-bearing plasmids has resulted in various genetic contexts of mcr-1 gene. In general, ISApl1 is flanked with mcr-1, and involves its transposition 97-99. The mcr-1-pap2 cassette (pap2 encodes a putative PAP2-like family of transmembrane protein) is neighbored with two (or one) ISApl1 (Rare case occurs without ISApl1). It seems likely that the ISApl1 whose location is downstream of mcr-1 is not as stable as it does in the upstream of mcr-1. In some instances, it can be completely (or partly) inverted, and even possess an insert sequence truncation. Similar scenarios were also seen with pap2 gene, indicating that PAP2, the product of pap2 is not prerequisite for MCR-1 colistin resistance 100. Apart from ISApl1, IS1 might also appear upstream of the mcr-1 gene. The genetic environment of mcr-2 is similar to that of mcr-1 because that it is adjacent to two IS1595 elements. In mcr-3-bearing plasmids, the transposon TnAs2 is located upstream of nimC/nimA-mcr-3 92, 94. In the mcr-4-positive ColE10-type plasmid, the IS5 element (ISKpn6) occurs upstream of mcr-4. As for the mcr-5 gene, it is carried within a Tn3-family transposon harbored on a 12-kb ColE-type plasmid 96. 9



Mechanisms of MCR-1/2 The outer membrane of Gram-negative bacteria contains negatively-charged LPS-lipid A moieties in its outer leaflet that act as the primary target for cationic polypeptide antibiotics like colistin and polymyxin B. Historically, it was understood that colistin relies upon the disruption of the integrity and permeability of the bacterial outer membrane 13. Therefore, colistin resistance arises from in part (if not all) from the inability of colistin to bind the outer membrane with altered LPS-lipid A moieties 101, 102

. In fact, the attachment of PEA to 1(4′)-phosphate position of glucosamine

moieties of LPS-lipid A is an effective way to reduce the net negative charge on bacterial membrane (Fig. 3A) 77, 103, leading to resistance to the cationic antibiotic polymyxin. This chemical modification is generally catalyzed by members of PEA-lipid A transferase family.

The Neisseria EptA is a paradigm of PEA-lipid A transferases, comprising two unique motifs: a transmembrane (TM) region and an enzymatic core domain. Structural dissection suggests a possible “ping-pong” mechanism for PEA modification of lipid A by EptA, in which an intermediate of EptA-bound PEA might occur (in first-half reaction, PEA is donated by PE, giving EptA-bound PEA; in second-half reaction, lipid A is a receiver of PEA from an adduct of EptA-bound PEA) 104, 105

. In similarity to the chromosomally-encoded EptA, the two plasmid-borne

MCR proteins (MCR-1 and MCR-2) are also annotated as PEA-lipid A transferases 10


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displaying conserved structural properties (Figs 3B & C). Structurally-guided site-directed mutagenesis has identified the in vivo role of the catalytic motif in MCR-1(MCR-2) colistin resistance (Figs 3B-D). The six residues required for the zinc-bound catalytic domain separately refer to E246, T285, H395, D465, H466 & H478 for MCR-1 (Figs 3B & D) 77 (E244, T283, H393, D463, H464 & H476 for MCR-2 (Figs 3C & D) 103).

Domain swapping shows that the two domains of MCR-1 are equivalent to that in MCR-2 (Figs 4A & B) 103. Genetic deletion assays also show that the TM region of MCR-1 (MCR-2) is essential to its physiological function (Fig. 4C) 77, 103. Combined with colistin susceptibility assays, MALDI-TOF MS analyses of LPS-lipid A pools confirm that none of point-mutants of MCR-1(MCR-2) with defective catalytic domains are functional PEA-lipid A enzymes. Together with other research groups 106-109, we also define a zinc-requiring catalytic motif in MCR-1 (MCR-2), which is critical for the enzymatic hydrolysis of PE by MCR-1/2 as well as its resultant colistin resistance 77, 103. Thus, EptA and MCR-1/2 remodel bacterial surfaces rendering them resistant to colistin.

Conclusions This mini-review aims to update the current understanding of diversified dissemination of MCR-1 colistin resistance. The complicated mechanisms involved in the spread of MCR-1 indicates that this transferability might be a tough challenge to 11



conquer. Given that new MCR-like genes are being increasingly detected, we believe that an environmental fluctuation/alteration with unknown selection pressure is causing their rapid evolution. This might partially stem from the indiscriminate prophylactic use of antibiotics in animal husbandry. Mechanistic insights into MCR-1/2 colistin resistance might provide better clues that might lead to the development of small molecule drugs/inhibitors targeting antibiotic resistance via bypassing the enzymatic activity of MCR-1/2. Because that different MCR-like enzymes share similar architectures of enzymatically-catalytic domains, it is of possibility to design a common inhibitor inactivating different MCR-like proteins. Given the subcellular localization of MCR-like enzymes in bacterial inner-membrane, the drug development in the future might consider potential barriers for drug delivery. In summary, the use of colistin in agriculture and clinical therapy needs strict re-evaluation and guidelines. Since the resistance in pathogens often co-evolves with the antibiotic pressure, a combination therapy with appropriate regimens of colistin that deliver the best clinical efficacy while minimizing toxicity might warrant further studies 110. As of formulating this manuscript, there is not any reported case of an ineffective colistin therapy in patients carrying mcr-positive bacteria yet. Thus, it might be a remaining question in this field.

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Abbreviations MCR-1, Mobilized colistin resistance determinant 1; MDR: Multi-drug resistance; CPE: Carbapenemase-producing Enterobacteriaceae; CRE: Carbapenem-resistant Enterobacteriaceae; NDM: New Delhi Metallo-β-lactamase; VIM: Verona Integron-Mediated Metallo-β-lactamase; ESBL: Extended-Spectrum β-Lactamases; IS: Insertion sequence; TM: Transmembrane region; PEA: Phosphoethanolamine; K. pneumoniae: Klebsiella pneumoniae; A. baumannii: Acinetobacter baumannii. Author Information Youjun Feng (PhD) Professor of Microbiology Department of Medical Microbiology and Parasitology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, PR China Conflict of Interest I declare that no conflict of interest is present. Acknowledgements The work in this lab was supported by National Key R&D Program of China (2017YFD0500202), National Key Basic Research Program of China (2016YFC1200100) and the National Natural Science Foundation of China (31570027 & 81772142). Dr. Feng is a recipient of the “Young 1000 Talents” Award. I would like to thank Dr. Swaminath Srinivas and Mr. Vishnu Goutham Kota for critical reading this manuscript.

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95. Carattoli A, V. L., Feudi C, Curcio L, Orsini S, Luppi A, Pezzotti G, Magistrali CF. (2017) Novel plasmid-mediated colistin resistance mcr-4 gene in Salmonella and Escherichia coli, Italy 2013, Spain and Belgium, 2015 to 2016, Euro Surveill 22 (31). pii: 30589. 96. Maria Borowiak, J. F., Jens A. Hammerl, Rene S. Hendriksen, Istvan Szabo and Burkhard Malorny. (2017) Identification of a novel transposon-associated phosphoethanolamine transferase gene, mcr-5, conferring colistin resistance in d-tartrate fermenting Salmonella enterica subsp. enterica serovar Paratyphi B, J Antimicrob Chemother 72(12):3317-3324. 97. Snesrud, E., He, S., Chandler, M., Dekker, J. P., Hickman, A. B., McGann, P., and Dyda, F. (2016) A model for transposition of the colistin resistance gene mcr-1 by ISApl1, Antimicrob Agents Chemother 60, 6973-6976. 98. Poirel, L., Kieffer, N., and Nordmann, P. (2017) In-vitro study of ISApl1-mediated mobilization of the colistin resistance gene mcr-1, Antimicrob Agents Chemother 61 (7). pii: e00127-17. 99. Snesrud, E., Ong, A. C., Corey, B., Kwak, Y. I., Clifford, R., Gleeson, T., Wood, S., Whitman, T. J., Lesho, E. P., Hinkle, M., and McGann, P. (2017) Analysis of serial isolates of mcr-1-positive Escherichia coli reveals a highly active ISApl1 transposon, Antimicrob Agents Chemother 61 (5). pii: e00056-17. 100. Zurfluh, K., Kieffer, N., Poirel, L., Nordmann, P., and Stephan, R. (2016) Features of the mcr-1 cassette related to colistin resistance, Antimicrob Agents Chemother 60, 6438-6439. 101. Petrou, V. I., Herrera, C. M., Schultz, K. M., Clarke, O. B., Vendome, J., Tomasek, D., Banerjee, S., Rajashankar, K. R., Belcher Dufrisne, M., Kloss, B., Kloppmann, E., Rost, B., Klug, C. S., Trent, M. S., Shapiro, L., and Mancia, F. (2016) Structures of aminoarabinose transferase ArnT suggest a molecular basis for lipid A glycosylation, Science 351, 608-612. 102. Hankins, J. V., Madsen, J. A., Giles, D. K., Brodbelt, J. S., and Trent, M. S. (2012) Amino acid addition to Vibrio cholerae LPS establishes a link between surface remodeling in gram-positive and gram-negative bacteria, PNAS 109, 8722-8727. 103. Sun, J., Xu, Y., Gao, R., Lin, J., Wei, W., Srinivas, S., Li, D., Yang, R. S., Li, X. P., Liao, X. P., Liu, Y. H., and Feng, Y. (2017) Deciphering MCR-2 colistin resistance, mBio 8 (3). pii: e00625-17. 104. Anandan, A., Evans, G. L., Condic-Jurkic, K., O'Mara, M. L., John, C. M., Phillips, N. J., Jarvis, G. A., Wills, S. S., Stubbs, K. A., Moraes, I., Kahler, C. M., and Vrielink, A. (2017) Structure of a lipid A phosphoethanolamine transferase suggests how conformational changes govern substrate binding, PNAS 114, 2218-2223. 105. Wanty, C., Anandan, A., Piek, S., Walshe, J., Ganguly, J., Carlson, R. W., Stubbs, K. A., Kahler, C. M., and

Vrielink,

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(2013)

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phosphoethanolamine transferase A (LptA) required for resistance to polymyxin, J Mol Biol 425, 3389-3402. 106. Ma, G., Zhu, Y., Yu, Z., Ahmad, A., and Zhang, H. (2016) High resolution crystal structure of the catalytic domain of MCR-1, Sci Rep 6, 39540. 107. Hu, M., Guo, J., Cheng, Q., Yang, Z., Chan, E. W., Chen, S., and Hao, Q. (2016) Crystal structure of Escherichia coli originated MCR-1, a phosphoethanolamine transferase for colistin resistance, Sci Rep 6, 38793. 108. Hinchliffe, P., Yang, Q. E., Portal, E., Young, T., Li, H., Tooke, C. L., Carvalho, M. J., Paterson, N. G., Brem, J., Niumsup, P. R., Tansawai, U., Lei, L., Li, M., Shen, Z., Wang, Y., Schofield, C. J., Mulholland, A. J., Shen, J., Fey, N., Walsh, T. R., and Spencer, J. (2017) Insights into the mechanistic basis of plasmid-mediated colistin resistance from crystal structures of the 21



catalytic domain of MCR-1, Sci Rep 7, 39392. 109. Stojanoski, V., Sankaran, B., Prasad, B. V., Poirel, L., Nordmann, P., and Palzkill, T. (2016) Structure of the catalytic domain of the colistin resistance enzyme MCR-1, BMC Biol 14, 81. 110. Zhou, Y. F., Tao, M. T., Feng, Y., Yang, R. S., Liao, X. P., Liu, Y. H., and Sun, J. (2017) Increased activity of colistin in combination with amikacin against Escherichia coli co-producing NDM-5 and MCR-1, J Antimicrob Chemother 72(6), 1723-1730. 111. AbuOun, M., Stubberfield, E. J., Duggett, N. A., Kirchner, M., Dormer, L., Nunez-Garcia, J., Randall, L. P., Lemma, F., Crook, D. W., Teale, C., Smith, R. P., and Anjum, M. F. (2017) mcr-1 and mcr-2 variant genes identified in Moraxella species isolated from pigs in Great Britain from 2014 to 2015, J Antimicrob Chemother 72, 2745-2749. 112. Teo, J. W. P., Kalisvar, M., Venkatachalam, I., Tek, N. O., Lin, R. T. P., and Octavia, S. (2017) mcr-3 and mcr-4 variants in carbapenemase-producing clinical Enterobacteriaceae do not confer phenotypic polymyxin resistance, J Clin Microbiol, pii: JCM.01562-17.

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For Table of Contents Use Only Table 1 Diversity of mcr-like genes Genes

Length (aa)

Plasmid

Bacteria

Origin

Country

Acc. no.

Ref.

541

pHNSHP4 5 (IncI2, 64015 bp)

E. coli

Swine

China

ANH55937

1

541 (Q3L)

pMCR1.2IT (IncX4, 33.3 kb)

K. pneumoniae

Rectal swab of child

Italy

WP_065274 078

67

541 (I38V)

pHeN867 (IncI2, 60,757 bp)

E. coli

Chicken

China

WP_077064 885

68

541 (D440N)

pMCR_W CHEC161 8

E. coli

/

China

KY463454

/

541 (H452Y)

pMCR-M 19241 (IncI1)

E. coli

Clinical isolate

Argentina/Ca nada

ARX60875

69

541 (R536H)

pMCR1.6 _P053 (IncP)

S. enterica

Healthy individu al

China

WP_077248 208

61

mcr-1.7

541 (A215T)

pMCR_W CHEC160 4-IncI2

E. coli

Sewage isolate

China

WP_085562 392

/

mcr-1.8

541 (Q3R)

/

E. coli

Poultry

Brunei

NG_054697

/

mcr-1.9

541 (V413A)

pLV23529 -MCR-1.9 (IncX4)

E. coli

Swine

Portugal

KY964067

/

mcr-1.10

541 (M2V, R11C, A23S, M155V, M234T, A354T, A443T)

Genomic DNA

Moraxella sp. MSG13-C03

Pig caecal contents

United Kingdom

MF176238

111

mcr-1.11

542 (with an additional V8)

Genomic DNA

E. coli

Human blood

Peru

NG_055784

/

mcr-1.12

541 (Q3H)

Genomic DNA

E. coli EC15-101

Pig

Japan

LC337668

/

pKP37-BE (IncX4, 35104 bp)

E. coli

Pig

Belgium

NG_051171

63

mcr-1

mcr-1.2

mcr-1.3

mcr-1.4

mcr-1.5

mcr-1.6

mcr-2

538

23



mcr-2.1

mcr-2.2

mcr-3

538

Genomic DNA

Moraxella pluranimaliu m

538

Genomic DNA pWJ1 (IncHI2, 261119)

541

Page 24 of 33

70

Pig

Spain

ASK49941

Moraxella sp. MSG47-C17

Pig

UK

ASK49942

70

E. coli

Pig

China

NG_055505

64

EC15 Contig67 (4732 bp)

E. coli

Pig, Vulval swab

Malaysia

NZ_JWKH 01000067

64

Contig (3346 bp)

S. enterica

Human stool

USA

NZ_NAAS 01000133

64

Contig (3501 bp)

K. pneumoniae

Human pus

Thailand

NZ_FLWZ 01000042

64

mcr-3.2

541 (D295E)

Contig (2631 bp)

K. pneumoniae

Human urine

Thailand

NZ_FLWO 01000034

64

mcr-3.3

541 (G373V)

Genomic DNA

K. pneumoniae

Human pus

Thailand

NG_055492

/

mcr-3.4

541 (M23V)

/

Citrobacter freundii

Pig

China

NG_055497

/

mcr-3.5

541 (T488I)

SNTR36B 6 (IncHI2)

E. coli

Human blood

Denmark

ERR197173 5

72

mcr-3.6

540 (M13I, D41Y, I71V, S117N, V122G, E139D, R297L, I313V, E337K, H341Y, G428A, L458M, Q468K, T488I, V493M, D494N, A496E, Q500M, K501N, D504A, T505N, S525A, V526I, K529Q, G530E, S535K, V540N)

Genomic DNA

Aeromonas veronii

Leucisc us idus

Germany

AST36140

/

541 (M23V, A457E, T488I)

pMCR3_L L123 (TnAs3/ IncP, 52.2 kb)

E. coli

Patient

China

MF489760

73

mcr-3.7

24


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mcr-3.8

540 (M13I, V122G, R297L, I313V, E337K, H341Y, D358E, G428A, L458M, Q468K, T488I, V493M, D494N, A496E, Q500M, K501N, D504A, T505N, S525A, V526I, K529Q, G530E, S535K, V540N)

Genomic DNA

Aeromonas hydrophila

Cyprinu s carpio

Germany

MF598079

/

mcr-3.9

541 (M13I, I71V, V122G, E144K, L151I, R297L, I313V, E337K, H341Y, D358E, Q468K)

Genomic DNA

Aeromonas hydrophila

Cyprinu s carpio

Germany

NG_055663

/

Genomic DNA

Aeromonas caviae

Cloaca

China

NG_055799

/

mcr-3.10

541 (V122G, R297L, I313V, E337K, H341Y, D358E, Q468K)

Genomic DNA

E. coli

Cloaca

China

MG214533

/

541 (Q468T)

Genomic DNA

E. coli

/

China

NG_056184

/

mcr-4

541

pMCR_R3 445 (8,749 bp)

Salmonella

Pig

Italy

MF543359

65

mcr-4.2

541 (Q331R)

Genomic DNA

S. enterica

Italy

MG581979

/

mcr-4.3 (Rename d from mcr-4.2)

541 (V179G, V236F)

Genomic DNA

Enterobacter cloacae

/

Singapore

MG026621

112

547

pSE13-SA 01718 & pSE12-02 541 (Tn3 transposon from ColEtype plasmid)

S. enterica subsp. entericaserov ar Paratyphi B

Poultry/ chicken meat

mcr-3.11

mcr-5

Human feces

25


KY807921 Germany

66

KY807920


The symbol “/” denotes “not applied”

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Figure Legends

Fig. 1 Structures of two leading types of polymyxins A. Chemical structure of polymyxin B B. Chemical structure of colistin (polymyxin E) Red letters in red denoted positive charges. Using ChemDraw, it was adapted in part from Sun and coworkers’ finding 103 with permission of Copyright [2017, ASM publisher/mBio].

27



Fig. 2 Complex dissemination of five mcr-like genes A. Unexpected complexity in diversified mcr-1-harbouring plasmids B. Transfer of mcr-2 by the IncX4-type plasmid pKP37-BE C. Carriage of mcr-3 in two types of plasmids The two types of mcr-3-positive plasmids referred to IncHI2-type plasmid pWJ1 and IncP-like plasmid pMCR3_LL123. D. Discovery of mcr-4, a new mobilized colistin resistance gene in the ColE10-type plasmid pMCR-R3445 E. The novel mcr-5 colistin resistance gene encoded by the two ColE10-type plasmids pSE12-02541 and pSE13-SA01718

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Fig. 3 Mechanistic insights into MCR-1/2 colistin resistance A. Working model for PEA modification of lipid A by MCR-1/2 Structural basis for the catalytic motif of MCR-1 (B) and MCR-2 (C) D. Structure-guided site-directed mutagenesis analyses for the putative active sites of MCR-1/2 It was adapted in part from Sun and coworkers’ finding 103 with permission of Copyright [2017, ASM publisher/mBio].

30


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Fig. 4 Functional dissection of TM regions in MCR-1/2 A. Scheme for domain swapping of MCR-1 and MCR-2 B. Functional analyses of the chimeric variants of MCR-1/2 on LBA plates supplied with various level of colistin C. Transmembrane domain of MCR-1/2 is prerequisite for the phenotypic colistin resistance It was adapted in part from Sun and coworkers’ finding 103 with permission of Copyright [2017, ASM publisher/mBio].

31



Graphic for TOC Colistin resistance in MCR-1-harboring E. coli

32


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Colistin resistance in MCR-1-harboring E. coli 215x115mm (300 x 300 DPI)


2 Polymyxin Resistance: Complex

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