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.
Highlights
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
To quantify the dynamics of resistance evolution for many different genotypes and replicates, we developed an automated platform that monitors the growth of hundreds of bacterial cultures while tightly controlling conditions and key evolution parameters (Fig. 1, see Methods)
If the bacterial population cannot endure the sustained antibiotic stress, the antibiotic concentration is automatically decreased until the growth rate has recovered to 50%
Summary
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. Require novel strategies that anticipate the evolutionary potential of pathogens and funnel them toward less evolvable genotypes or evolutionary dead ends To this end, it is promising to identify genetic factors and cellular mechanisms that do not immediately increase a pathogen’s resistance but rather determine its ability to evolve[13,14,15,16]. High-level resistance for specific antibiotics such as quinolones can be gained by mutations in the drug target, preventing antibiotic binding[24] In this case, increased mutation rates can accelerate resistance evolution[25]. Interfering with different cellular functions can sensitize or protect cells[35] and alter the initial state in resistance evolution How do such targeted perturbations of cellular functions interact with the subsequent evolutionary adaptation to drugs?
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