DNA Double-Strand Break Formation and Repair as Targets for Novel Antibiotic Combination Chemotherapy

Abstract

An unrepaired DNA double-strand break (DSB) is lethal to cells. In bacteria, DSBs are usually repaired either via an error-prone pathway, which ligates the ends of the break or an accurate recombination pathway. Due to this lethality, drugs that induce persistent DSBs have been successful in bacterial infection treatment. However, recurrent usage of these drugs has led to emergence of resistant strains. Several articles have thoroughly reviewed the causes, mechanisms and effects of bacterial drug resistance while others have also discussed approaches for facilitating drug discovery and development. Here, we focus on a hypothetical chemotherapeutic strategy that can be explored for minimizing development of resistance to novel DSB-inducing compounds. We also highlight the possibility of utilizing bacterial DSB repair pathways as targets for the discovery and development of novel antibiotics.

Lay abstract

Our health systems face a huge challenge in the form of antimicrobial resistance, which may result in many common infections becoming untreatable. The same antibiotics that gave modern medicine its power are fast losing their hold on the germs that cause disease. Many options are being developed to restore the control that antibiotics have on the microbes that cause many diseases. In this perspective, we outline a concept that is built around the way and manner in which bacteria mend their DNA whenever there is a break in the DNA chain. We discuss the merits of finding a new class of drugs that obstruct bacterial ability to mend their broken DNA. In this scenario, a combination of these new drugs with existing drugs or other new drugs that cause breaks in bacterial DNA would become a powerful therapeutic regimen. This concept, when fully developed, will offer hope in our effort to combat antimicrobial-resistant infections.

Keywords:

• antibiotic combination chemotherapy
• cell-based assays
• DNA double-strand break
• genome stability
• homologous recombination
• nonhomologous end joining
• quinolone resistance
• ribosome inhibitors
• SOS response
• type II topoisomerase

Acknowledgments

The authors acknowledge J Herrmann of the Helmholtz Institute for Pharmaceutical Research Saarland for critical reading the manuscript.

Financial & competing interests disclosure

V Amarh and PK Arthur were supported by funds from a World Bank African Centres of Excellence grant (ACE02-WACCBIP: Awandare) and a DELTAS Africa grant (DEL-15-007: Awandare). The DELTAS Africa Initiative is an independent funding scheme of the African Academy of Sciences's Alliance for Accelerating Excellence in Science in Africa and supported by the New Partnership for Africa's Development Planning and Coordinating Agency (NEPAD Agency) with funding from the Wellcome Trust (107755/Z/15/Z: Awandare) and the UK government. The views expressed in this publication are those of the author(s) and not necessarily those of African Academy of Sciences, NEPAD Agency, Wellcome Trust or the UK government. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.