Adaptive Processes Change as Multiple Functions Evolve

Abstract

Epistasis influences the gene-environment interactions that shape bacterial fitness through antibiotic exposure which can ultimately affect the availability of certain resistance phenotypes to bacteria. The substitutions present within blaTEM-50 confer both cephalosporin and β-lactamase inhibitor resistance. We wanted to compare the evolution of blaTEM-50 with another variant, blaTEM-85, which differs in that blaTEM-85 contains only substitutions that contribute to cephalosporin resistance. Differences between the landscapes and epistatic interactions of these TEM variants are important for understanding their separate evolutionary responses to antibiotics. We hypothesized the substitutions within blaTEM-50 would result in more epistatic interactions than blaTEM-85. As expected, we found more epistatic interactions between the substitutions present in blaTEM-50 than in blaTEM-85. Our results suggest that selection from many cephalosporins is required to achieve the full potential resistance to cephalosporins, but that a single β-lactam and inhibitor combination will drive evolution of the full potential resistance phenotype. Surprisingly, we also found significantly positive increases in growth rates as antibiotic concentration increased for some of the strains expressing blaTEM-85 precursor genotypes but not the blaTEM-50 variants. This result further suggests additive interactions more effectively optimize phenotypes than epistatic interactions which means that exposure to numerous cephalosporins actually increases the ability of a TEM enzyme to confer resistance to any single cephalosporin.

Evolution of antibiotic resistance impacts optimal temperature and growth rate in Escherichia coli and Staphylococcus epidermidis

“…Because nitrofurantoin has multiple mechanisms of action, resistance can be caused by different mutational pathways leading to resistance, or epistasis. Epistasis has been shown to play a major role in the diversity of antibiotic resistance genes (Levin‐Reisman et al, 2019; Mira et al, 2015; Mira et al, 2021; Østman et al, 2012; Santos‐Lopez et al, 2019; Schenk et al, 2013). The range of antibiotic mechanism of action and potential epistatic interactions across resistance genes could help explain the multiple phenotypic outcomes observed in nitrofurantoin‐resistant E. coli .…”

Allogenous Selection of Mutational Collateral Resistance: Old Drugs Select for New Resistance Within Antibiotic Families

“…Antibiotic synergistic pleiotropy within families could eventually accelerate the development of resistance, because of the simultaneous evolution of resistance traits. It has been shown that those additive interactions and epistatic interactions resulting from exposure to different cephalosporins increase the ability of a TEM enzyme to provide higher fitness to the host cell than any single cephalosporin (Mira et al, 2021). The predictability of resistance phenotypes resulting from mutations to different antibiotics (Knopp and Andersson, 2018) suggests that a similar approach could be applied to mutations within a single antibiotic family.…”

Epistasis decreases with increasing antibiotic pressure but not temperature

“…With epistasis, interactions can be specific between particular mutations due to mechanistic interactions of residues or proteins, for example (reviewed in [ 26 ]), or global, where any combination of mutations ultimately shows a pattern of G × G [ 27 , 28 ]. In contrast to increasing numbers of reports of ubiquitous epistasis [ 12 , 29 , 30 ], much existing work to date has considered single ABR genotypes at a time under the assumptions of additive effects (but see [ 31 , 32 ]). The theoretical concept of a fitness landscape, which maps every possible genotype to its fitness, captures G × G interactions and enables the study of how such interactions affect evolutionary trajectories (reviewed in [ 2 , 33 ]).…”