Abstract
The emergence and dissemination of antibiotic resistance threaten the treatment of common bacterial infections. Resistance genes are often encoded on conjugative elements, which can be horizontally transferred to diverse bacteria. In order to delay conjugative transfer of resistance genes, more information is needed on the genetic determinants promoting conjugation. Here, we focus on which bacterial host factors in the donor assist transfer of conjugative plasmids. We introduced the broad-host-range plasmid pKJK10 into a diverse collection of 113 Escherichia coli strains and measured by flow cytometry how effectively each strain transfers its plasmid to a fixed E. coli recipient. Differences in conjugation efficiency of up to 2.7 and 3.8 orders of magnitude were observed after mating for 24 h and 48 h, respectively. These differences were linked to the underlying donor strain genetic variants in genome-wide association studies, thereby identifying candidate genes involved in conjugation. We confirmed the role of fliF, fliK, kefB and ucpA in the donor ability of conjugative elements by validating defects in the conjugation efficiency of the corresponding lab strain single-gene deletion mutants. Based on the known cellular functions of these genes, we suggest that the motility and the energy supply, the intracellular pH or salinity of the donor affect the efficiency of plasmid transfer. Overall, this work advances the search for targets for the development of conjugation inhibitors, which can be administered alongside antibiotics to more effectively treat bacterial infections.
Highlights
Introduction iationsAntibiotic resistance poses a major challenge to human health
Our goal was to identify host factors in the donor cell that are involved in conjugation by associating the diversity in E. coli phenotypes with the diversity in genotypes
E. coli strains consisting of 1 lab strain, 59 strains isolated from different wild animals and 53 strains isolated from different human individuals (27 clinical isolates, 16 strains originating from healthy individuals and 10 strains of humans of unknown health)
Summary
4.95 million deaths globally in 2019 was associated with antibiotic resistance, including. 1.27 million deaths attributed directly to antibiotic resistance [1]. Among Escherichia coli, the cause of enteric/diarrhoeal disease, urinary tract infections and sepsis/meningitis, more than half of the isolates (57.1%) in the European Economic Area reported to EARS-Net in 2019 were resistant to at least one of the antimicrobial groups under surveillance, underscoring the wide spread of resistance [2,3]. Approved antibiotics and candidate drugs in the clinical pipeline should be shielded for as long as possible against the fast emergence and dissemination of resistance [4]. In this respect, conjugative DNA elements are especially problematic as they are notorious for capturing, retaining and spreading antibiotic resistance genes [5,6].
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