A transferable IncC-IncX3 hybrid plasmid co-carrying bla_NDM-4, tet(X4), and tmexCD3-toprJ3 confers resistance to carbapenem and tigecycline

Abstract

Tigecycline is a last-resort antimicrobial that exhibits promising activity against carbapenemase-producing Enterobacterales (CPE). However, mobile tigecycline resistance genes, tet(X) and tmexCD-toprJ, have emerged in China and have spread possibly worldwide. Tet(X) family proteins, Tet(X3) to Tet(X14), function as tigecycline-inactivating enzymes, and TMexCD-TOprJ complexes function as efflux pumps for tigecycline. Here, we report a CPE isolate co-harboring both emerging tigecycline resistance factors for the first time. A carbapenem- and tigecycline-resistant Klebsiella aerogenes NUITM-VK5 was isolated from an urban drainage in Vietnam in 2021 and a plasmid pNUITM-VK5_mdr co-carrying tet(X4) and tmexCD3-toprJ3 along with the carbapenemase gene blaNDM-4 was identified in NUITM-VK5. pNUITM-VK5_mdr was transferred to Escherichia coli by conjugation and simultaneously conferred high-level resistance against multiple antimicrobials, including carbapenems and tigecycline. An efflux pump inhibitor canceled TMexCD3-TOprJ3-mediated tigecycline resistance, suggesting that both tigecycline resistance factors independently and additively contribute to the high-level resistance. The plasmid had the IncX3 and IncC replicons and was estimated to be a hybrid of plasmids with different origins. Unlike IncX3 plasmids, IncC plasmids are stably maintained in an extremely broad range of bacterial hosts in humans, animals, and environment. Thus, future global spread of multidrug-resistance plasmids such as pNUITM-VK5_mdr poses a public health crisis.

Coexistence of tet (X4), mcr-1 , and bla NDM-5 in ST6775 Escherichia coli Isolates of Animal Origin in China

“…Therefore, tet (X4)-bearing structure may be able to form recombinant plasmids with other plasmids carrying IS CR2 or IS 26 , which frequently appear on many MDR plasmids, such as bla NDM-5 -bearing IncX3 plasmids or mcr-1 -harboring IncHI2 plasmids. The cocarriage of tet (X6) and mcr-1 by a single IncHI2 plasmid ( 28 ), and the cocarriage of bla NDM-4 , tet (X4), and tmexCD3-toprJ3 genes by a single IncC-IncX3 hybrid plasmid, have been found previously ( 22 ). Previously, we also proved that a single hybrid plasmid bearing mcr-1 and tet (X4) may appear under the mediation of insertion sequences ( 29 ).…”

“…Recently, the bla NDM-5 -bearing IncX3 plasmid was reported to coexist with tet (X4)-harboring plasmid in one isolate ( 21 ). There was even one strain in which the bla NDM-4 , tet (X4) and tmexCD3-toprJ3 genes were in a single IncC-IncX3 hybrid plasmid ( 22 ). The emergence of isolates’ resistance to carbapenem and tigecycline makes the clinical treatment of carbapenem-resistant pathogens challenging.…”

Emergence of plasmid-mediated RND-type efflux pump gene cluster tmexCD-toprJ in Shewanella xiamenensis in a water environment

“…aerogenes in our previous report that was isolated from the same area (7), suggesting that they might share a common ancestor. Our results provide genetic evidence that clinically important ARGs have been disseminated though plasmids, such as broad-host-range IncC plasmids, and their fusion plasmids among environmental bacteria, such as Shewanella species, in aquatic environments.…”

“…In 2021, we reported a Klebsiella aerogenes isolate harboring a selftransferable incompatibility group C (IncC)-IncX3 hybrid plasmid co-carrying blaNDM-4, tet(X4), and tmexCD3-toprJ1 [initially named tmexCD3-toprJ3 (5) and 5 later renamed (6)] from a water environment in Vietnam (7). Although the Flavobacteriaceae family is estimated as the natural reservoir of tet(X) genes ( 8), limited information is available on the distribution of tmexCD-toprJ in the natural environment.…”

IncC plasmid genome rearrangements influence the vertical and horizontal transmission tradeoff inEscherichia coli

“…Most of the diversity in IncC plasmid genomes results from changes, confined to a few hotspots of integration, consisting of differences within horizontally acquired accessory genes (in particular the gain and deletion of resistance genes) and/or loss of adjacent backbone regions (3,(7)(8)(9). Some type 1/2-hybrid IncC plasmids have been described, arising from homologous recombination events between the two groups of IncC plasmids, or multireplicon composite IncC plasmids, resulting from the integration of a plasmid belonging to another incompatibility group into the IncC plasmid genome (9)(10)(11).…”