Antimutator and mutational spectrum effects can combine to reduce evolutionary potential in Escherichia coli ΔnudJ.

Authors

R Green, H Richards, D Ozbilek, F Tyrrell, V Barton, Z Zhang, S C Lovell, D R Gifford, M Lagator, A J McBain, R Krašovec, C G Knight

Published in

Molecular biology and evolution. Jul 29, 2025. Epub Jul 29, 2025.

Abstract

The rate of spontaneous mutation is a key factor in determining the capacity of a population to adapt to a novel environment, for example a bacterial population exposed to antibiotics. Genetic and environmental factors controlling the mutation rate commonly also cause shifts in the relative rates of different mutational classes, i.e. the mutational spectrum. When the mutational spectrum is altered, the relatively enriched and depleted mutations may differ in their fitness effects. Here we explore how a reduced mutation rate and altered mutational spectrum can contribute to adaptation in Escherichia coli. We measure mutation rates across a set of Nudix hydrolase deletants, finding multiple strains with an antimutator phenotype. We focus on the antimutator ΔnudJ which can cause a 6-fold mutation rate reduction relative to the wildtype, with an altered mutational spectrum biased towards A>C transversions. Its reduced mutation rate, most pronounced at low population densities, appears to occur via NudJ's role in nucleotide and/or prenyl metabolism, with a reduced internal ATP pool. Its effects may be reversed by mutations to genes, including waaZ, affecting the outer membrane. Not only does nudJ deletion reduce the probability of antibiotic resistance arising at all but, through enhancing an existing hotspot for low fitness A>C rifampicin resistance mutations, reduces the expected fitness of strains when resistance does arise. Thus our findings with ΔnudJ suggest future anti-evolution drug strategies could suppress spontaneous resistance evolution, not only through minimising resistance mutations, but also by specifically limiting access to the fittest mutations.

PMID:
40729517
Bibliographic data and abstract were imported from PubMed on 30 Jul 2025.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.