Adaptive Resistance Mutations at Suprainhibitory Concentrations Independent of SOS Mutagenesis

Ricardo Gutiérrez, Yoav Ram, Judith Berman, Keyla Carstens Marques De Sousa, Yaarit Nachum-Biala, Malka Britzi, Daniel Elad, Gad Glaser, Shay Covo, Shimon Harrus*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


Emergence of resistant bacteria during antimicrobial treatment is one of the most critical and universal health threats. It is known that several stress-induced mutagenesis and heteroresistance mechanisms can enhance microbial adaptation to antibiotics. Here, we demonstrate that the pathogen Bartonella can undergo stress-induced mutagenesis despite the fact it lacks error-prone polymerases, the rpoS gene and functional UV-induced mutagenesis. We demonstrate that Bartonella acquire de novo single mutations during rifampicin exposure at suprainhibitory concentrations at a much higher rate than expected from spontaneous fluctuations. This is while exhibiting a minimal heteroresistance capacity. The emerged resistant mutants acquired a single rpoB mutation, whereas no other mutations were found in their whole genome. Interestingly, the emergence of resistance in Bartonella occurred only during gradual exposure to the antibiotic, indicating that Bartonella sense and react to the changing environment. Using a mathematical model, we demonstrated that, to reproduce the experimental results, mutation rates should be transiently increased over 1,000-folds, and a larger population size or greater heteroresistance capacity is required. RNA expression analysis suggests that the increased mutation rate is due to downregulation of key DNA repair genes (mutS, mutY, and recA), associated with DNA breaks caused by massive prophage inductions. These results provide new evidence of the hazard of antibiotic overuse in medicine and agriculture.

Original languageAmerican English
Pages (from-to)4095-4115
Number of pages21
JournalMolecular Biology and Evolution
Issue number10
StatePublished - 1 Oct 2021

Bibliographical note

Publisher Copyright:
© 2021 The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.


  • Bartonella
  • antibiotic resistance
  • evolution
  • rifampicin
  • slow-growing bacteria


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