Bacterial Mutation Rates and Antibiotic Resistance

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A new study reports that bacterial mutation rates are significantly higher under crowded conditions and offers insights which could help develop methods to counter antibiotic resistance.

Mutations, or changes in the DNA sequence, create genetic variations which can be beneficial or deleterious and are essential for the evolution of organisms. In fact, genetic mutations are what fuel evolution.  Bacterial mutation rates can vary between species and even between different strains of the same species. They can differ widely depending on the composition of the base sequence, the availability of repair factors, and environmental factors such as exposure to mutagens. A study published in 2014 found another environmental factor, population density, and reported that the mutation rate in Escherichia coli that gave rise to resistance to the antibiotic rifampicin was inversely related to population density. In fact, mutation rates increased at least three-fold when population density was lowered.1

The same group of researchers examined the literature published over the past 70 years to determine the relationship between mutation rates and population density. They also experimentally tested this relationship in cultures of E. coli, Pseudomonas aeruginosa, and Saccharomyces cerevisiae using the fluctuation test, which was used to determine mutation rates. A report detailing their findings was recently published in PLOS Biology.2

After a thorough analysis of published data on mutation rates from 26 different species and 68 studies dating back 70 years, the authors found that there was a clear negative relationship between population density and mutation rate: across all organisms, the mutation rate doubled with a 64% decline in population density. To verify that the changes in mutation rates were due to changes in population density and not other reasons, the researchers carried out experiments to measure mutation rates in E. coli that generate resistance to the antibiotics rifampicin and nalidixic acid and in S. cerevisiae to hygromycin B and 5-fluoroorotic acid. These experiments confirmed that variations in mutation rates were linked to population density.

In other experiments, the researchers tried to pinpoint the molecular mechanisms involved in population density associated variations in mutation rate. They carried out site-directed mutagenesis experiments targeting various polymerases involved in DNA replication and repair, DNA repair enzymes that correct for base mismatches, and enzymes that remove mutagenic nucleotides and prevent their incorporation into DNA. Of all the genes tested, deleting the mutT gene, encoding for 8-oxo-dGTP diphosphatase that converts the oxidized mutagenic nucleotide 8-oxo-dGTP to a monophosphate, was found to decouple the dependence of mutation rate on population density. A similar effect was observed for the deletion of the PCD1 gene (coding for the enzyme peroxisomal coenzyme A diphosphatase 1 in S. cerevisiae), which is the functional homolog of bacterial mutT.

This study has important implications for evolutionary biology and the study of antibiotic resistance.  Overall, these results indicate that population density associated variations in the mutation rate is a common feature of living organisms, and even viruses. Additionally, the decoupling of the mutation rate from the population density by deleting mutT and PCD1 suggests that conserved mechanisms are involved in the process. Finally, bacterial mutations give rise to antibiotic resistance; therefore, insights gained from this study and future studies investigating the role of population density linked mutation rate variability in evolution could help address the problem of antibiotic resistance.

Written by Usha B. Nair, Ph.D.

References:

  1. Krašovec R, Belavkin RV, Aston JA, Channon A, Aston E, Rash BM, Kadirvel M, Forbes S, Knight CG. Mutation rate plasticity in rifampicin resistance depends on Escherichia coli cell-cell interactions. Nat Commun. 2014 Apr 29;5:3742. doi: 10.1038/ncomms4742. PubMed PMID: 24776982; PubMed Central PMCID: PMC4007418.
  2. Krašovec R, Richards H, Gifford DR, Hatcher C, Faulkner KJ, Belavkin RV, Channon A, Aston E, McBain AJ, Knight CG. Spontaneous mutation rate is a plastic trait associated with population density across domains of life. PLoS Biol. 2017 Aug 24;15(8):e2002731. doi: 10.1371/journal.pbio.2002731. eCollection 2017 Aug. PubMed PMID: 28837573; PubMed Central PMCID: PMC5570273.



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