Role of RelA-synthesized (p)ppGpp and ROS-induced mutagenesis in de novo acquisition of antibiotic resistance in E. coli

• Published in: iScience 2024-04, Vol.27 (4), p.109579-109579, Article 109579
• Main Authors: Qi, Wenxi, Jonker, Martijs J., de Leeuw, Wim, Brul, Stanley, ter Kuile, Benno H.
• Format: Article
• Language: English
• Subjects: Microbiology; Molecular biology
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2024.109579

The stringent response of bacteria to starvation and stress also fulfills a role in addressing the threat of antibiotics. Within this stringent response, (p)ppGpp, synthesized by RelA or SpoT, functions as a global alarmone. However, the effect of this (p)ppGpp on resistance development is poorly understood. Here, we show that knockout of relA or rpoS curtails resistance development against bactericidal antibiotics. The emergence of mutated genes associated with starvation and (p)ppGpp, among others, indicates the activation of stringent responses. The growth rate is decreased in ΔrelA-resistant strains due to the reduced ability to synthesize (p)ppGpp and the persistence of deacylated tRNA impeding protein synthesis. Sluggish cellular activity causes decreased production of reactive oxygen species (ROS), thereby reducing oxidative damage, leading to weakened DNA mismatch repair, potentially reducing the generation of mutations. These findings offer new targets for mitigating antibiotic resistance development, potentially achieved through inhibiting (p)ppGpp or ROS synthesis. [Display omitted] •Deletion of relA or rpoS results in a decelerated acquisition of resistance to bactericidal antibiotics•Resistant strains exhibit mutations in genes linked to antibiotic resistance, oxidative stress, the SOS response, and the stringent response•Knockout of relA leads to reduced ROS production and mitigated DNA oxidative damage•Transcription levels of genes involved in DNA repair are diminished in ΔrelA-resistant strains exposed to bactericidal antibiotics Molecular biology; Microbiology