Stepwise evolution and convergent recombination underlie the global dissemination of carbapenemase-producingEscherichia coli

Abstract

26Carbapenem-resistant Enterobacteriaceae are considered by WHO as "critical" priority 27 pathogens for which novel antibiotics are urgently needed. The dissemination of 28 carbapenemase-producing Escherichia coli (CP-Ec) in the community is a major public 29 health concern. However, the global molecular epidemiology of CP-Ec isolates, as well as 30 the genetic bases for the emergence and global dissemination of specific lineages, 31 remain largely unknown. Here, by combining a thorough genomic and evolutionary 32 analysis of Ec ST410 isolates with a broad analysis of 12,584 E. coli and Shigella 33 genomes, we showed that the fixation of carbapenemase genes depends largely on a 34 combination of mutations in ftsI encoding the penicillin binding protein 3 and in the 35 porin genes ompC and ompF. Mutated ftsI genes and a specific ompC allele inducing 36 reduced susceptibility to diverse β-lactams spread across the species by recombination. 37The selection of CP-Ec lineages able to disseminate is more complex than the mere 38 acquisition of carbapenemase genes. 39 40 41 Antibiotic resistance is one of the most urgent public health concerns. The 42 increasing rate in antimicrobial resistances worldwide suggests a bleak outlook in terms 43 of morbidity, mortality and economic loss 1 . Carbapenems are one of the last resort 44 antibiotics used to treat infections caused by multidrug-resistant (MDR) Gram-negative 45 bacteria 2 . Dissemination of carbapenem-resistant Enterobacteriaceae (CRE) threatens 46 the efficacy of current treatment options. Carbapenem-resistance may result from a 47 combination of mutations leading to reduced permeability (e.g. porin deficiency) and 48 overexpression of an extended-spectrum β-lactamase (ESBL) or a cephalosporinase that 49 show a weak activity against carbapenems 3 . However, the main resistance mechanism is 50 the acquisition of a carbapenemase gene 4 . The major carbapenemases encountered in 51Enterobacteriaceae belong to Ambler class A (KPC-type), class B (metallo-β-lactamases 52 IMP, VIM-and NDM-types) or class D (OXA-48-like enzymes) 5 . As these carbapenemases 53 are now frequently encountered in Escherichia coli, carbapenemase-producing E. coli 54 (CP-Ec) might follow the same expansion and dissemination in hospitals and the 55 community as the one observed for CTX-M-type ESBL-producing E. coli isolates 6,7 . A 56 scenario feared by public health authorities. This is especially worrisome as these 57 isolates are usually resistant to multiple antibiotics. 58The epidemiology of CP-Ec is complex with geographical diversity in terms of 59 carbapenemase genes and of dominant lineages 4 . Most studies performed at national or 60 hospital levels point to a broad diversity of isolates as defined by multilocus sequence 61 typing (MLST), with some isolates belonging to a few dominant sequence types (STs) 62 like ST38, clonal complex (CC) 10 (ST10, ST167, ST617), ST101, ST131 and ST410 that 63 express different carbapenemases 4,[8][9][10][11][12][13][14] . However, their prevalence vari...

Population Analysis of Escherichia coli Sequence Type 361 and Reduced Cefiderocol Susceptibility, France

“…Two isolates had a different allele with a YRIK insertion and an A412V substitution, and 2 isolates had no insertions or mutations. Of note, the 3 different alleles were associated with 3 different nodes on the phylogenetic tree, indicating an evolution process that probably involved chromosomal recombination (Figure 2), as described for ST410 (11). The YRIN(K) motif insertion has been described to be involved in cephalosporin and aztreonam resistance (8,9,11).…”

“…Of note, the 3 different alleles were associated with 3 different nodes on the phylogenetic tree, indicating an evolution process that probably involved chromosomal recombination (Figure 2), as described for ST410 (11). The YRIN(K) motif insertion has been described to be involved in cephalosporin and aztreonam resistance (8,9,11). To study the effect of the YRIN(K) motif insertion on cefiderocol resistance, we performed susceptibility testing on the reference strain and its isogenic PBP3 encoding gene mutant with YRIN insertion (11).…”

“…gov/EID/article/29/9/23-0390-App1.pdf) (10). E. coli ST410, ST167, and ST405 have been characterized at the genomic level (3,8,11), but ST361 characteristics remain unclear.…”

“…gov/EID/article/29/9/23-0390-App1.pdf) (10). E. coli ST410, ST167, and ST405 have been characterized at the genomic level (3,8,11), but ST361 characteristics remain unclear.During July 1, 2021-June 30, 2022, we investigated all (n = 856) nonduplicate carbapenem-nonsusceptible E. coli isolates sent to F-NRC. We used Sensititer broth microdilution (ThermoFisher, https://www.…”

High-level ceftazidime-avibactam resistance inEscherichia coliconferred by the novel plasmid-mediated beta-lactamase CMY-185 variant

“…These FtsI substitutions have been associated with reduced susceptibility to CAZ and FEP, 24 ATM-AVI in the presence of blaCTX-M-15, 25 and associated with the acquisition of carbapenemases in ST410 backgrounds. 26 A full table of all acquired AMR genes detected in Ec1 -Ec3 is presented in Table 2. These results suggest that blaCMY-185 may have developed through selective pressures that beget mutations in a blaCMY-42 gene harbored on an IncI conjugative plasmid.…”