Quinolone drugs: investigating pathways of DNA damage repair and antibiotic resistance

Diez, Isabel (2022) Quinolone drugs: investigating pathways of DNA damage repair and antibiotic resistance. Doctoral thesis, University of East Anglia.

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Abstract

Quinolones are widely used antibiotics that target bacterial topoisomerases. These are essential enzymes that modify the topology of DNA by making double-strand breaks (DSBs). Quinolones bind to topoisomerase-DNA complexes trapping the topoisomerases on the DNA. This causes bacterial death due to the formation of DSBs. But when the levels of quinolones are not high enough to kill bacteria, they can lead to the acquisition of antibiotic resistance (AR) to quinolone and non-quinolone antibiotics.

The link between the mechanism of action of quinolones and the acquisition of AR is not clear. In this work I have investigated whether quinolone-induced antimicrobial resistance (QIAR) depended on the repair of quinolone-induced DNA damage. I have explored different pathways of repair and found that the protease Lon, the nuclease Exo VII, and the recombinase RecBCD might work together to, first, digest part of the trapped topoisomerase, then remove the topoisomerase from the DNA and finally to repair the DSB. I have also shown that the quinolone ciprofloxacin induced resistance to several non-quinolone antibiotics, such as chloramphenicol. This ciprofloxacin-induced chloramphenicol resistance was due to mutations (i.e., mutations in marR or amplifications of mdfA) that depended on the SOS response, a bacterial response to DNA damage. However, this QIAR phenomenon was not solely dependant on Exo VII, one of the proteins involved in the repair of quinolone-induced DNA damage, suggesting that QIAR can be caused by an alternative pathway of DNA repair.

These findings may aid our understanding of how quinolones kill bacteria and induce mutations. They may have implications in the use of quinolones, as targeting the SOS response would improve quinolone activity and prevent QIAR. Still, further studies on the biological and clinical implications of QIAR are needed.

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Science > School of Biological Sciences
Depositing User: Chris White
Date Deposited: 04 Jul 2022 12:56
Last Modified: 04 Jul 2022 12:56
URI: https://ueaeprints.uea.ac.uk/id/eprint/85927
DOI:

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