Adaptive Resistance Mutations at Suprainhibitory Concentrations Independent of SOS Mutagenesis

Molecular Biology and Evolution - Tập 38 Số 10 - Trang 4095-4115 - 2021
Ricardo Gutiérrez1,2, Yoav Ram3,4, Judith Berman5, Keyla Carstens Marques de Sousa2, Yaarit Nachum‐Biala2, Malka Britzi6, D. Elad7, Gad Glaser8, Shay Covo9, Shimon Harrus2
1The Center for Research in Tropical Diseases, Faculty of Microbiology, University of Costa Rica, San José, Costa Rica
2The Koret School of Veterinary Medicine, Faculty of Agriculture, The Hebrew University of Jerusalem, Rehovot, Israel
3School of Computer Science, Interdisciplinary Center Herzliya, Herzliya, Israel
4School of Zoology, Faculty of Life Sciences, Tel Aviv University, Ramat Aviv, Israel
5Shmunis School of Biomedicine and Cancer, Faculty of Life Sciences, Tel Aviv University, Ramat Aviv, Israel
6The National Residue Control Laboratory, The Kimron Veterinary Institute, Bet Dagan, Israel
7Department of Clinical Bacteriology and Mycology, The Kimron Veterinary Institute, Bet Dagan, Israel
8Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, The Hebrew University of Jerusalem, Jerusalem, Israel
9Department of Plant Pathology and Microbiology, Faculty of Agriculture, The Hebrew University of Jerusalem, Rehovot, Israel

Tóm tắt

Abstract 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.

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Molecular Biology and Evolution

Tập 38 Số 10

4095-4115

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