Reversing resistance: different routes and common themes across pathogens

Abstract

Resistance spreads rapidly in pathogen or pest populations exposed to biocides, such as fungicides and antibiotics, and in many cases new biocides are in short supply. How can resistance be reversed in order to prolong the effectiveness of available treatments? Some key parameters affecting reversion of resistance are well known, such as the fitness cost of resistance. However, the population biological processes that actually cause resistance to persist or decline remain poorly characterized, and consequently our ability to manage reversion of resistance is limited. Where do susceptible genotypes that replace resistant lineages come from? What is the epidemiological scale of reversion? What information do we need to predict the mechanisms or likelihood of reversion? Here, we define some of the population biological processes that can drive reversion, using examples from a wide range of taxa and biocides. These processes differ primarily in the origin of revertant genotypes, but also in their sensitivity to factors such as coselection and compensatory evolution that can alter the rate of reversion, and the likelihood that resistance will re-emerge upon re-exposure to biocides. We therefore argue that discriminating among different types of reversion allows for better prediction of where resistance is most likely to persist.

Keywords: antimicrobials; biocides; fungicides; reversing resistance.

Figure 1.

Alternative pathways to reversion. The grey rectangle represents a pathogen or pest, the black circle its genome. Resistance alleles are shown in red, other genetic changes affecting resistance in blue, and genetic variation at other loci in yellow. Resistance acquired by (a) mutation or (b) horizontal gene transfer may be reverted through isogenetic, paragenetic, or allogenetic processes. Some processes involve genetic changes to the prevailing genotype (isogenetic reversion via mutation or loss of horizontally transferred elements; paragenetic reversion), while others involve the prevailing genotype being replaced by a competing lineage of the same strain or species that is either the same as the ancestral genotype (isogenetic reversion via regrowth or reinvasion) or different (allogenetic reversion).

Figure 2.

Within-host reversion is influenced by transmission and local adaptation. Two susceptible pathogen lineages (shaded and unshaded ovals; see legend) are unevenly distributed across two patches or hosts (large grey circles). Lightning indicates past treatment with a biocide that is no longer present, but favours costly resistant genotypes (red outline) that can emerge on either lineage. Size of the ovals represents expected fitness in the present host or patch; black arrows show possible pathways to reversion. (a) High transmission and costly resistance allow reversion by any process described above. (b) Lower transmission reduces the influx of susceptibles from other hosts/patches and the likelihood of coinfection, preventing both allogenetic reversion and isogenetic reversion by reinvasion. (c) Resistant genotypes are also locally adapted to their present host or patch, diminishing the competitive advantage of susceptibles and preventing isogenetic reversion by regrowth or reinvasion and allogenetic reversion resulting from outcompetition by coinfecting or superinfecting susceptibles; here the most likely reversion pathway is by mutation or gene loss (large white oval with black outline). Compensatory adaptation (not shown) will also reduce the advantage of susceptibles and the likelihood of reversion. (d) Biocide treatment across all hosts or patches reduces the supply of susceptible genotypes, making reversion through pathways requiring migration/gene flow less likely.