Dataset Information

Anti-HIV agent azidothymidine decreases Tet(X)-mediated bacterial resistance to tigecycline in Escherichia coli.

ABSTRACT: Recent emergence of high-level tigecycline resistance mediated by Tet(X3/X4) in Enterobacteriaceae undoubtably constitutes a serious threat for public health worldwide. Antibiotic adjuvant strategy makes antibiotic more effective against these resistant pathogens through interfering intrinsic resistance mechanisms or enhancing antibiotic actions. Herein, we screened a collection of drugs to identify compounds that are able to restore tigecycline activity against resistant pathogens. Encouragingly, we discovered that anti-HIV agent azidothymidine dramatically potentiates tigecycline activity against clinically resistant bacteria. Meanwhile, addition of azidothymidine prevents the evolution of tigecycline resistance in E. coli and the naturally occurring horizontal transfer of tet(X4). Evidence demonstrated that azidothymidine specifically inhibits DNA synthesis and suppresses resistance enzyme activity. Moreover, in in vivo infection models by Tet(X4)-expression E. coli, the combination of azidothymidine and tigecycline achieved remarkable treatment benefits including increased survival and decreased bacterial burden. These findings provide an effective regimen to treat infections caused by tigecycline-resistant Escherichia coli.

SUBMITTER: Liu Y

PROVIDER: S-EPMC7125129 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Anti-HIV agent azidothymidine decreases Tet(X)-mediated bacterial resistance to tigecycline in Escherichia coli.

Liu Yuan Y Jia Yuqian Y Yang Kangni K Li Ruichao R Xiao Xia X Wang Zhiqiang Z

Communications biology 20200403 1

Recent emergence of high-level tigecycline resistance mediated by Tet(X3/X4) in Enterobacteriaceae undoubtably constitutes a serious threat for public health worldwide. Antibiotic adjuvant strategy makes antibiotic more effective against these resistant pathogens through interfering intrinsic resistance mechanisms or enhancing antibiotic actions. Herein, we screened a collection of drugs to identify compounds that are able to restore tigecycline activity against resistant pathogens. Encouragingl ...[more]

PMID: 32246108

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Project description: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.

Project description:Emergence of pathogens harboring tigecycline resistance genes incurs great concerns. Wastewater is recognized as the important reservoir of antimicrobial resistance genes. Here we characterized the phenotypes and genotypes of bacteria carrying tet(X4) from wastewater in Turkey for the first time. Four tet(X4)-positive Escherichia coli isolates were identified and characterized by PCR, Sanger sequencing, antimicrobial susceptibility testing, conjugation assays, Illumina sequencing, nanopore sequencing and bioinformatic analysis. Four tet(X4)-harboring isolates were multidrug-resistant (MDR) bacteria and the tet(X4) gene was nontransferable in four isolates. Genetic analysis revealed that tet(X4) genes in four isolates were located on plasmids co-harboring two replicons IncFIA(HI1) and IncFIB(K). However, none of the four plasmids carried genes associated with horizontal transfer of plasmids. The coexistence of blaSHV-12-bearing IncX3-type plasmid and tet(X4)-harboring plasmid was also found in one isolate. These findings indicate that continuous surveillance of the tet(X4)-bearing isolates in different environments worldwide should be strengthened. IMPORTANCE The emergence of tigecycline resistance genes in humans and animals in China seriously threatens the clinical utility of tigecycline, but the molecular epidemiology of tigecycline-resistant bacteria in other countries remained largely unknown. Therefore, it is necessary to learn the prevalence and molecular characteristics of bacteria carrying tigecycline resistance genes, particularly the mobilizable tet(X4), in other countries. In the study, we first described the presence and molecular characteristics of the tet(X4)-positive E. coli isolates from wastewater in Turkey. Four tet(X4)-bearing isolates belonged to ST609, an E. coli clone commonly found from humans, animals and the environment. These findings highlight the importance of monitoring the tet(X4) gene in different settings globally.

Dataset Information

Anti-HIV agent azidothymidine decreases Tet(X)-mediated bacterial resistance to tigecycline in Escherichia coli.

Publications

Anti-HIV agent azidothymidine decreases Tet(X)-mediated bacterial resistance to tigecycline in Escherichia coli.

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