Tigecycline Sensitivity Reduction in Escherichia coli Due to Widely Distributed tet(A) Variants

Shan Zhang; Mingquan Cui; Dejun Liu; Bo Fu; Tingxuan Shi; Yang Wang; Chengtao Sun; Congming Wu

doi:10.3390/microorganisms11123000

Tigecycline Sensitivity Reduction in Escherichia coli Due to Widely Distributed tet(A) Variants

Microorganisms. 2023 Dec 18;11(12):3000. doi: 10.3390/microorganisms11123000.

Authors

Shan Zhang^{1

2}, Mingquan Cui³, Dejun Liu^{1

2}, Bo Fu^{1

2}, Tingxuan Shi^{1

2}, Yang Wang^{1

2}, Chengtao Sun^{1

2}, Congming Wu^{1

2}

Affiliations

¹ National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China.
² Key Laboratory of Animal Antimicrobial Resistance Surveillance, Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China.
³ China Institute of Veterinary Drug Control, Beijing 100081, China.

Abstract

Despite scattered studies that have reported mutations in the tet(A) gene potentially linked to tigecycline resistance in clinical pathogens, the detailed function and epidemiology of these tet(A) variants remains limited. In this study, we analyzed 64 Escherichia coli isolates derived from MacConkey plates supplemented with tigecycline (2 μg/mL) and identified five distinct tet(A) variants that account for reduced sensitivity to tigecycline. In contrast to varied tigecycline MICs (0.25 to 16 μg/mL) of the 64 tet(A)-variant-positive E. coli isolates, gene function analysis confirmed that the five tet(A) variants exhibited a similar capacity to reduce tigecycline sensitivity in DH5α carrying pUC19. Among the observed seven non-synonymous mutations, the V55M mutation was unequivocally validated for its positive role in conferring tigecycline resistance. Interestingly, the variability in tigecycline MICs among the E. coli strains did not correlate with tet(A) gene expression. Instead, a statistically significant reduction in intracellular tigecycline concentrations was noted in strains displaying higher MICs. Genomic analysis of 30 representative E. coli isolates revealed that tet(A) variants predominantly resided on plasmids (n = 14) and circular intermediates (n = 13). Within China, analysis of a well-characterized E. coli collection isolated from pigs and chickens in 2018 revealed the presence of eight tet(A) variants in 103 (4.2%, 95% CI: 3.4-5.0%) isolates across 13 out of 17 tested Chinese provinces or municipalities. Globally, BLASTN analysis identified 21 tet(A) variants in approximately 20.19% (49,423/244,764) of E. coli genomes in the Pathogen Detection database. These mutant tet(A) genes have been widely disseminated among E. coli isolates from humans, food animals, and the environment sectors, exhibiting a growing trend in tet(A) variants over five decades. Our findings underscore the urgency of addressing tigecycline resistance and the underestimated role of tet(A) mutations in this context.

Keywords: Escherichia coli; tet(A) variants; tigecycline resistance.

Grants and funding

32002340/National Natural Science Foundation of China