Frequent convergence of mcr-9 and carbapenemase genes in Enterobacter cloacae complex driven by epidemic plasmids and host incompatibility

Abstract

Convergence of mcr and carbapenemase genes has been sporadically detected in Enterobacter cloacae complex (ECC) with an upward trend. However, the state of the epidemic and underlying mechanism of such convergence has been poorly understood. In this study, the co-occurrence of MCR and carbapenemases was systematically analyzed in 230 clinical ECC isolates collected between 2000 and 2018 together with a global dataset consisting of 3,559 ECC genomes compiled from GenBank. We identified 48 mcr-9 / mcr-10 -positive isolates (MCR-ECC) (20.9%) in our collection, and a comparable ratio of MCR-ECC (720/3559, 20.2%) was detected in the global dataset. A high prevalence of carbapenemase-producing MCR-ECC (MCR-CREC) was further identified in the MCR-ECC of both datasets (16/48, 33.3%; 388/720, 53.9%), demonstrating a frequent convergence of mcr-9/10 and carbapenemase genes in ECC worldwide. An epidemic IncHI2/2A plasmid with a highly conserved backbone was identified and largely contributed to the dissemination of mcr-9 in ECC worldwide. A highly conserved IncX3-type NDM-1-carrying plasmid and IncN-type IMP-4-carrying plasmid were additionally detected in MCR-CREC isolated in China. Our surveillance data showed that MCR-CREC emerged (in 2013) much later than MCR-ECC (in 2000), indicating that MCR-CREC could be derived from MCR-ECC by additional captures of carbapenemase-encoding plasmids. Tests of plasmid stability and incompatibility showed that the mcr-9/mcr-10 -encoding plasmids with the NDM-1-encoding plasmids stably remained in ECC but incompatible in Escherichia coli , suggesting that the convergence was host-dependent. The findings extend our concern on the convergence of resistance to the last resort antibiotics and highlight the necessity of continued surveillance in the future.

Emergence of colistin-resistant Enterobacter cloacae and Raoultella ornithinolytica carrying the phosphoethanolamine transferase gene, mcr-9 , derived from vegetables in Japan

“…Transconjugants with high colistin MIC were obtained when conjugating pCST17-2_1, indicating that mcr-9 was located on a self-transferable plasmid ( Table 2 ). This observation is consistent with previous reports that the worldwide dissemination of mcr-9 is mainly driven by HI2/HI2A plasmids ( 18 , 48 , 49 ). Furthermore, similar conjugative mcr-9 -carring plasmids have been found in food and clinical isolates in Japan ( 34 , 43 , 61 ), suggesting a One Health perspective on the transmission of such mcr homolog.…”

“…Multiple Enterobacterial species, including Salmonella ( 45 ), E. coli ( 45 ), E. asburiae ( 50 ), Citrobacter telavivum ( 51 ), and E. hormaechei ( 52 ) with the so-called qseBC genes, have been reported to exhibit colistin-susceptible phenotypes. In contrast, some other studies also found that lack of such a tandem system in certain bacterial species was associated with colistin-resistant phenotypes, as with E. roggenkampii ( 34 ), E. cloacae complex ( 48 ), and S . Newport ( 35 ).…”

“…mcr-9 has been found in multiple bacterial species, including S. enterica ( 44 , 45 ), E. coli ( 32 , 45 ), E. hormaechei ( 40 , 46 ), Enterobacter kobei / Enterobacter asburiae ( 47 ), and K. pneumoniae ( 43 ), and is mostly hosted in the E. cloacae complex isolated from humans and animals ( 48 ). Understanding the transmission routes and mechanisms of resistance is crucial for making tailored decisions to controlling the spread of mcr alleles.…”

Molecular epidemiology and genomic characterization of a plasmid-mediated mcr-10 and blaNDM-1 co-harboring multidrug-resistant Enterobacter asburiae

“…strains were found successively in different types of plasmids (IncFII, IncFIB, IncFIB, and IncFIA) [11] , [20] , [21] and different species, including E. cloacae , E. kobei , E. asburiae , E. ludwigii , and E. hormaechei [22] . Compared to mcr-10 , mcr-9 has a higher isolation rate from conserved plasmid types (IncHI2/2 A) in ECC strains and usually coexisted with carbapenemase genes [18] . Moreover, in a recent report, mcr-9 was co-transferred with bla NDM-1 among ECC strains, although transconjugants did not show resistance to colistin [23] .…”

“…E. asburiae is widely isolated throughout the United States due to the horizontal transfer of bla IMI-2 carbapenemase gene between clinical and river environments [17] . A study collected mcr-9/10 positive E. asburiae showed that sequence type (ST) 484 mcr-9 -carrying E. asburiae strains were dominant (29.4%, 10/34) [18] . Besides, ST252 E. asburiae was reported as the predominant reservoir of a new transferable quinolone resistance qnrE family allele gene qnr Eas1 [19] .…”