The plasmid‐borne quinolone resistance protein QnrB, a novel DnaA‐binding protein, increases the bacterial mutation rate by triggering DNA replication stress

Abstract

Summary Bacterial 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.

Pentapeptide repeat protein QnrB1 requires ATP hydrolysis to rejuvenate poisoned gyrase complexes

“…Models were proposed in which PRPs bind to the positively charged GyrA dimer ( 19 , 22 ). In more recent pull-down experiment ( 48 ), GST-tagged QnrB1 protein was shown to bind E. coli GyrB stronger than GyrA. Likewise, in two-hybrid system experiments the QnrB1 interaction signal for GyrB was 7- to 11-fold higher than the signal for GyrA ( 49 ).…”

Transferable Mechanisms of Quinolone Resistance from 1998 Onward

“…Nonetheless, a study published in 2019 showed that qnrB has a general mutator effect in both the presence and the absence of ciprofloxacin and also showed that QnrB interacts with DnaA, subsequently regulating the formation of the DnaA-oriC complex and leading to the upregulation of genes near oriC. This results in DNA replication stress, which in turn favors both an increase in the number of plasmids, independently of Qnr-topoisomerase interactions, and higher mutation rates (255). In the last years, the effect of TMQR on the further selection of quinolone resistance mechanisms and bacterial survival in the presence of lethal concentrations of quinolones has been analyzed (256)(257)(258).…”

Aqnr-plasmid allows aminoglycosides to induce SOS inEscherichia coli

“…In addition, it has also recently been shown that qnrB promotes DNA mutations and thereby fluoroquinolone-resistant mutants by triggering DNA replication stress. (Li et al, 2019) In this context, the SOS regulation of such PMQR genes have clinical implications, not only in term of infectious disease treatments, but also to prevent the dissemination of resistance genes. It has been clearly demonstrated that the qnrB-mediated quinolone resistance is induced upon exposure to sub-MICs of fluoroquinolone (Re et al, 2009).…”