Imperial College London
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DrAndrewEdwards

Faculty of Medicine, Department of Infectious Disease

Director of Postgraduate Education & Senior Lecturer
 
 
 
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Contact

 

a.edwards Website

 
 
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Location

 

5.40AFlowers buildingSouth Kensington Campus

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Summary

 

Publications

Citation

BibTex format

@article{Clarke:2019:10.1128/AAC.00944-19,
author = {Clarke, R and Bruderer, M and Ha, KP and Edwards, A},
doi = {10.1128/AAC.00944-19},
journal = {Antimicrobial Agents and Chemotherapy},
title = {RexAB is essential for the mutagenic repair of Staphylococcus aureus DNA damage caused by co-trimoxazole},
url = {http://dx.doi.org/10.1128/AAC.00944-19},
volume = {63},
year = {2019}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Co-trimoxazole (SXT) is a combination therapeutic that consists of sulfamethoxazole and trimethoprim that is increasingly used to treat skin and soft-tissue infections caused by methicillin-resistant Staphylococcus aureus (MRSA). However, the use of SXT is limited to the treatment of low-burden, superficial S. aureus infections and its therapeutic value is compromised by the frequent emergence of resistance. As a first step towards the identification of approaches to enhance the efficacy of SXT, we examined the role of bacterial DNA repair in antibiotic susceptibility and mutagenesis. We found that mutants lacking the DNA repair complex RexAB had a modest 2-fold lower SXT MIC than wild-type strains but were killed 50-5000-fold more efficiently by the combination antibiotic at the breakpoint concentration. SXT-mediated DNA damage occurred via both thymidine limitation and the generation of reactive oxygen species, and triggered induction of the SOS response in a RexAB-dependent manner. SOS induction was associated with a 50% increase in the mutation rate, which may contribute to emergence of resistant strains during SXT therapy. In summary, this work determined that SXT caused DNA damage in S. aureus via both thymidine limitation and oxidative stress, which was repaired by the RexAB complex, leading to induction of the mutagenic SOS response. Small molecule inhibitors of RexAB could therefore have therapeutic value by increasing the efficacy of SXT and decreasing the emergence of drug-resistance during treatment of infections caused by S. aureus.
AU  - Clarke,R
AU  - Bruderer,M
AU  - Ha,KP
AU  - Edwards,A
DO  - 10.1128/AAC.00944-19
PY  - 2019///
SN  - 0066-4804
TI  - RexAB is essential for the mutagenic repair of Staphylococcus aureus DNA damage caused by co-trimoxazole
T2  - Antimicrobial Agents and Chemotherapy
UR  - http://dx.doi.org/10.1128/AAC.00944-19
UR  - https://aac.asm.org/content/early/2019/10/01/AAC.00944-19/article-info
UR  - http://hdl.handle.net/10044/1/74394
VL  - 63
ER  -
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