Abstract
SummaryBacterial antibiotic resistance, a global health threat, is caused by plasmid transfer or genetic mutations. Quinolones are important antibiotics, partially because they are fully synthetic and resistance genes are unlikely to exist in nature; nonetheless, quinolone resistance proteins have been identified. The mechanism by which plasmid‐borne quinolone resistance proteins promotes the selection of quinolone‐resistant mutants is unclear. Here, we show that QnrB increases the bacterial mutation rate. Transcriptomic and genome sequencing analyses showed that QnrB promoted gene abundance near the origin of replication (oriC). In addition, the QnrB expression level correlated with the replication origin to terminus (oriC/ter) ratio, indicating QnrB‐induced DNA replication stress. Our results also show that QnrB is a DnaA‐binding protein that may act as an activator of DNA replication initiation. Interaction of QnrB with DnaA promoted the formation of the DnaA‐oriC open complex, which leads to DNA replication over‐initiation. Our data indicate that plasmid‐borne QnrB increases bacterial mutation rates and that genetic changes can alleviate the fitness cost imposed by transmitted plasmids. Derivative mutations may impair antibiotic efficacy and threaten the value of antibiotic treatments. Enhanced understanding of how bacteria adapt to the antibiotic environment will lead to new therapeutic strategies for antibiotic‐resistant infections.
Highlights
Bacterial antibiotic resistance is a significant threat to the prevention of infectious diseases (Davies, 1994; Berendonk et al, 2015; Kling et al, 2015; Morehead and Scarbrough, 2018) that generally results from plasmid transfer or genetic mutations (Toprak et al, 2011; San Millan, 2018)
Quinolones are important antibiotics, partially because they are fully synthetic and resistance genes are unlikely to exist in nature; quinolone resistance proteins have been identified
The mechanism by which plasmid-borne quinolone resistance proteins promotes the selection of quinolone-resistant mutants is unclear
Summary
Bacterial antibiotic resistance is a significant threat to the prevention of infectious diseases (Davies, 1994; Berendonk et al, 2015; Kling et al, 2015; Morehead and Scarbrough, 2018) that generally results from plasmid transfer or genetic mutations (Toprak et al, 2011; San Millan, 2018). Plasmids drive the horizontal transfer of antibiotic resistance genes, and compensatory mutations can alleviate the fitness cost imposed by the transmitted plasmid (Gama et al, 2018; San Millan, 2018). Interactions between plasmids and the bacterial chromosome impact the spread of antibiotic resistance (Gama et al, 2018). Resistance to quinolones was thought to be caused by mutation of their target genes (encoding DNA gyrase and DNA topoisomerase IV) and/or changes in cell wall permeability. It was assumed that no quinolone resistance genes existed naturally. It is known that quinolone resistance (Qnr) proteins cause low-level quinolone resistance and facilitate the selection of resistant mutants
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