The Emerging Role of (p)ppGpp in DNA Repair and Associated Bacterial Survival against Fluoroquinolones

(p)ppGpp binds to RNA polymerase, causing stalling at damaged DNA sites and subsequent backtracking, which facilitates the recognition and removal of damaged DNA by repair proteins. Additionally, (p)ppGpp regulates DNA repair proteins involved in the Save Our Soul response and mutagenic strand break repair pathways, which are crucial for repairing damages induced by Ultraviolet light and other DNA-damaging agents, including antibiotics. Through these repair pathways, (p) ppGpp plays a vital role in mending strand breaks induced by ciprofloxacin, a fluoroquinolone antibiotic. (p)ppGpp mediates bacterial survival by inhibiting the transcription of mismatch repair proteins while simultaneously upregulating error-prone polymerases mediated by stress-induced sigma factors, thereby facilitating mutagenesis. The function of (p)ppGpp in fine-tuning DNA repair proteins to support bacterial survival against antibiotics via stress-induced mutagenesis is an emerging topic in the field of antibiotic resistance research. Currently, limited information is available on how (p)ppGpp interconnects the various DNA repair pathways that directly influence bacterial resistance to antibiotics. (p)ppGpp is also known to promote bacterial persistence against ofloxacin, another fluoroquinolone, by regulating proteins that induce membrane depolarization. The overlapping functions of (p)ppGpp as a master regulator in DNA repair during stress and bacterial persistence are yet to be fully elucidated. This review focuses on recent publications highlighting (p)ppGpp as a potential link connecting DNA repair pathways to bacterial survival strategies against fluoroquinolone antibiotics.