Role of RelA-synthesized (p)ppGpp and ROS-induced mutagenesis in de novo acquisition of antibiotic resistance in E. coli
Summary: 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...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2024-04-01
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| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004224008010 |
| _version_ | 1827292091983593472 |
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| author | Wenxi Qi Martijs J. Jonker Wim de Leeuw Stanley Brul Benno H. ter Kuile |
| author_facet | Wenxi Qi Martijs J. Jonker Wim de Leeuw Stanley Brul Benno H. ter Kuile |
| author_sort | Wenxi Qi |
| collection | DOAJ |
| description | Summary: 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. |
| first_indexed | 2024-04-24T12:51:40Z |
| format | Article |
| id | doaj.art-fc72b00c30104d6f8352fa821e17ca20 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-04-24T12:51:40Z |
| publishDate | 2024-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-fc72b00c30104d6f8352fa821e17ca202024-04-06T04:40:19ZengElsevieriScience2589-00422024-04-01274109579Role of RelA-synthesized (p)ppGpp and ROS-induced mutagenesis in de novo acquisition of antibiotic resistance in E. coliWenxi Qi0Martijs J. Jonker1Wim de Leeuw2Stanley Brul3Benno H. ter Kuile4Laboratory for Molecular Biology and Microbial Food Safety, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, the NetherlandsRNA Biology & Applied Bioinformatics, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, the NetherlandsRNA Biology & Applied Bioinformatics, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, the NetherlandsLaboratory for Molecular Biology and Microbial Food Safety, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, the NetherlandsLaboratory for Molecular Biology and Microbial Food Safety, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, the Netherlands; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2589004224008010Molecular biologyMicrobiology |
| spellingShingle | Wenxi Qi Martijs J. Jonker Wim de Leeuw Stanley Brul Benno H. ter Kuile Role of RelA-synthesized (p)ppGpp and ROS-induced mutagenesis in de novo acquisition of antibiotic resistance in E. coli iScience Molecular biology Microbiology |
| title | Role of RelA-synthesized (p)ppGpp and ROS-induced mutagenesis in de novo acquisition of antibiotic resistance in E. coli |
| title_full | Role of RelA-synthesized (p)ppGpp and ROS-induced mutagenesis in de novo acquisition of antibiotic resistance in E. coli |
| title_fullStr | Role of RelA-synthesized (p)ppGpp and ROS-induced mutagenesis in de novo acquisition of antibiotic resistance in E. coli |
| title_full_unstemmed | Role of RelA-synthesized (p)ppGpp and ROS-induced mutagenesis in de novo acquisition of antibiotic resistance in E. coli |
| title_short | Role of RelA-synthesized (p)ppGpp and ROS-induced mutagenesis in de novo acquisition of antibiotic resistance in E. coli |
| title_sort | role of rela synthesized p ppgpp and ros induced mutagenesis in de novo acquisition of antibiotic resistance in e coli |
| topic | Molecular biology Microbiology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004224008010 |
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