Radial Expansion Facilitates the Maintenance of Double Antibiotic Resistances

Abstract

Most microbes live in spatially confined sub-populations. Under spatial structure, the efficacy of natural selection is often reduced (relative to homogeneous conditions), due to the increased importance of genetic drift and local competition. Additionally, under spatial structure, the fittest genotype may not always be the one with better access to the heterogeneous distribution of nutrients. The effect of radial expansion may be particularly relevant for the elimination of antibiotic resistance mutations, as their dynamics within bacterial populations are strongly dependent on their growth rate. Here, we use Escherichia coli to systematically compare the allele frequency of streptomycin, rifampicin and fluoroquinolone single and double resistance mutants after 24h of coexistence with a susceptible strain under radial expansion (local competition) and homogeneous (global competition) conditions. We show that there is a significant effect of structure on the maintenance of double resistances which is not observed for single resistances. Radial expansion also facilitates the persistence of double resistances when competing against their single counterparts. Importantly, we found that spatial structure reduces the rate of compensation of the double mutant RpsLK43TRpoBH526Y and that a strongly compensatory mutation in homogeneous conditions becomes deleterious under spatial structure. Overall, our results unravel the importance of spatial structure for facilitating the maintenance and accumulation of multiple resistances over time and for determining the identity of compensatory mutations.

The Neglected Contribution of Streptomycin to the Tuberculosis Drug Resistance Problem

“…The hypothesis that STR resistance can predispose to resistance to other drugs has been raised in different studies [ 19 , 37 , 38 , 90 ]. Research with Escherichia coli showed evidence pointing to a beneficial role in the combination of mutations associated with resistance to STR and RIF [ 91 , 92 ]. In these studies, it was shown that double-resistant STR and RIF E. coli can compensate for the fitness cost of drug resistance mutations faster than single-resistant bacteria [ 91 , 92 ].…”

“…Research with Escherichia coli showed evidence pointing to a beneficial role in the combination of mutations associated with resistance to STR and RIF [ 91 , 92 ]. In these studies, it was shown that double-resistant STR and RIF E. coli can compensate for the fitness cost of drug resistance mutations faster than single-resistant bacteria [ 91 , 92 ]. Interestingly, attention has been called to the fact that the STR resistant bacterial populations are more likely to have mutations that compensate for fitness costs than RIF resistant ones [ 92 ].…”

The within-host evolution of antimicrobial resistance in Mycobacterium tuberculosis

“…Recent in vitro work in E. coli shows that reduced competition due to spatial segregation may allow for the maintenance of multiple AMR mutations for longer durations compared to populations without spatial segregation (Durão et al . 2020 ). Thus, for the MTBC, low between-lesion migration levels would hypothetically lead to higher levels of MTBC genetic diversity and, consequently, higher likelihood of heteroresistance observed within TB patients.…”

Competition dynamics in long‐term propagations of Schizosaccharomyces pombe strain communities

“…environmental, and medical purposes. However, predicting how complex communities of microbes behave over large timescales is difficult since competition for scarce resources and limited space among diverse strains and species can be complex (Durão et al, 2020;Estrela & Brown, 2018;Ghoul & Mitri, 2016;Goldford et al, 2018;Hibbing et al, 2010;Pande & Kost, 2017;Pande et al, 2014).…”