Highly parallel lab evolution reveals that epistasis can curb the evolution of antibiotic resistance

Abstract

Genetic perturbations that affect bacterial resistance to antibiotics have been characterized genome-wide, but how do such perturbations interact with subsequent evolutionary adaptation to the drug? Here, we show that strong epistasis between resistance mutations and systematically identified genes can be exploited to control spontaneous resistance evolution. We evolved hundreds of Escherichia coli K-12 mutant populations in parallel, using a robotic platform that tightly controls population size and selection pressure. We find a global diminishing-returns epistasis pattern: strains that are initially more sensitive generally undergo larger resistance gains. However, some gene deletion strains deviate from this general trend and curtail the evolvability of resistance, including deletions of genes for membrane transport, LPS biosynthesis, and chaperones. Deletions of efflux pump genes force evolution on inferior mutational paths, not explored in the wild type, and some of these essentially block resistance evolution. This effect is due to strong negative epistasis with resistance mutations. The identified genes and cellular functions provide potential targets for development of adjuvants that may block spontaneous resistance evolution when combined with antibiotics.

The Population Genetics of Collateral Resistance and Sensitivity

“…We allow for an arbitrary correlation between home and non-home fitness. This form of the JDFE is consistent with our current understanding of the structure of global epistasis (Kryazhimskiy et al, 2014;Johnson et al, 2019;Lukačišinová et al, 2020 In this model, it is possible to obtain analytical expressions for the expected fitness trajectories of the population X t , Y t in the home and non-home environments (see Materials and Methods). As expected, our theory quantitatively predicts the fitness trajectories obtained in stochastic SSWM simulations ( Figure 3E).…”

Antimicrobial Resistance in Escherichia coli Strains Isolated from Humans and Pet Animals

“…It is absolutely clear to us today that the antibiotic resistance of E. coli and some other bacteria involves a combination of different factors [ 87 , 88 ]. Research results indicate that E. coli exhibits the strongest resistance to the longest used and most commonly prescribed antibiotics [ 89 , 90 , 91 ]. This is exactly the case with sulfonamides, which were first used in humans around 1930s [ 92 ].…”

Mapping the Role of AcrAB-TolC Efflux Pumps in the Evolution of Antibiotic Resistance Reveals Near-MIC Treatments Facilitate Resistance Acquisition

“…In addition, heterogeneity in efflux pump expression can predispose subsets of bacterial populations with elevated acrAB expression to mutation even prior to antibiotic treatment ( 34 ). Deletion of genes associated with efflux pumps, such as tolC , can also reduce evolvability under antibiotic exposure ( 35 ). Furthermore, a recent study in Staphylococcus aureus found that higher NorA pump levels increased evolvability and that addition of a pump inhibitor could prevent resistance evolution ( 36 ).…”