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.
Highlights
Synergy between inducer of double-strand break (DSB) and inhibitor of DSBRThe historic antibiotics, such as penicillin, streptomycin, chloramphenicol and tetracycline, were originally isolated from fungal sources or soil bacteria [8]
In US intensive care units: implications for fluoroquinolone use
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Summary
The historic antibiotics, such as penicillin, streptomycin, chloramphenicol and tetracycline, were originally isolated from fungal sources or soil bacteria [8]. The use of the paradigm cell-based assays is likely to continue to yield the same classes of antibiotics against the same range of targets for which resistance mechanisms already exist or have evolved. An alternative strategy would be to design cell-based and target-specific assays that detect new classes of compounds that act synergistically to inhibit the development of resistance. The problems associated with screening of natural products are the high dynamic range of compounds, in terms of chemical diversity and concentration. To address these issues, the new cell-based and target-specific assay ought to include strategies that improve on selectivity and sensitivity to many orders of magnitude.
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