Idiosyncratic variation in the fitness costs of tetracycline-resistance mutations inEscherichia coli

Abstract

A bacterium's fitness relative to its competitors, both in the presence and absence of antibiotics, plays a key role in its ecological success and clinical impact. In this study, we examine whether tetracycline-resistant mutants are less fit in the absence of the drug than their sensitive parents, and whether the fitness cost of resistance is constant or variable across independently derived lines. Tetracycline-resistant lines suffered, on average, a reduction in fitness of almost 8%. There was substantial among-line variation in the fitness cost. This variation was not associated with the level of phenotypic resistance conferred by the mutations, nor did it vary significantly across several different genetic backgrounds. The two resistant lines with the most extreme fitness costs involved functionally unrelated mutations on different genetic backgrounds. However, there was also significant variation in the fitness costs for mutations affecting the same pathway and even different alleles of the same gene. Our findings demonstrate that the fitness costs of antibiotic resistance do not always correlate with the phenotypic level of resistance or the underlying genetic changes. Instead, these costs reflect the idiosyncratic effects of particular resistance mutations and the genetic backgrounds in which they occur.

The Population Genetics of Collateral Resistance and Sensitivity

“…This variation suggests that bacteria and cancers have access to multiple resistance mutations with different collateral sensitivity profiles, such that replicates can accumulate different mutations simply due to the intrinsic randomness of the evolutionary process (Jerison et al, 2020). However, the variability of collateral effects among resistance mutations has not been characterized (but see Card et al, 2021), and there is no principled approach for accounting for this variability in designing robust multi-drug treatments. In particular, it is unclear which evolutionary parameters determine the expected collateral outcomes of evolution and, importantly, the uncertainty around these expectations.…”