ArticlePLoS genetics2026
Loss of DNA mismatch repair genes leads to acquisition of antibiotic resistance independent of secondary mutations.
Article in PLoS genetics, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Antibiotic resistant bacteria have been a major clinical concern for decades. Beyond acquisition of alleles conferring resistance, bacteria under stress (e.g., from changing environmental conditions or mutations) can have higher intrinsic resistance to antibiotics than unstressed cells. This concern is expanded for gram-negative bacteria which have a protective outer membrane that serves as an additional barrier against harmful molecules such as antibiotics. Here, we report a pathway which increases antibiotic resistance (i.e., minimum inhibitory concentration) in response to inactivation of the DNA Mismatch Repair pathway (MMR). This pathway led to increased intrinsic resistance and was independent of secondary mutations. Specifically, deletion of the DNA mismatch repair genes mutL or mutS caused resistance to various antibiotics spanning different classes, molecular sizes, and mechanisms of action in several different E. coli K-12 MG1655 strains, and in Salmonella enterica serovar Typhimurium LT2. This pathway did not change outer membrane permeability or efflux rates. However, the patterns of resistance in MMR mutants correlated with previously reported increases in rates of homoeologous recombination (homologous recombination between non-identical DNA strands). Mutations expected to lower rates of recombination in MMR mutants also decreased the resistance to some antibiotics. Finally, we found lysis occurs in MMR mutants and may contribute to resistance. Our results have demonstrated a novel mechanism that increases antibiotic resistance in direct response to loss of MMR genes, and we propose this resistance involves increased rates of homoeologous recombination and cell lysis. The increased antibiotic resistance of MMR mutants provides a path for these cells to survive in antibiotics long enough to develop more specific resistance mutations and so may contribute to the development of new clinical resistance alleles.
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