Allele-specific collateral and fitness effects determine the dynamics of fluoroquinolone-resistance evolution

Abstract

Collateral sensitivity (CS), which arises when resistance to one antibiotic increases sensitivity towards other antibiotics, offers novel treatment opportunities to constrain or reverse the evolution of antibiotic resistance. The applicability of CS-informed treatments remains uncertain, in part because we lack an understanding of the generality of CS effects for different resistance mutations, singly or in combination. Here we address this issue in the Gram-positive pathogen S. pneumoniae by quantifying collateral and fitness effects of a series of clinically relevant first-step (gyrA or parC) mutations, and their combinations, that confer resistance to fluoroquinolones. We integrated these results in a mathematical model which allowed us to evaluate how different in silico combination treatments impact the dynamics of resistance evolution. We identified common and conserved CS effects of different gyrA and parC mutations; however, the spectrum of collateral effects was unique for each mutation or mutation pair. This indicated that mutation identity, even different mutations to the same amino acid, can impact the evolutionary dynamics of resistance evolution during monotreatment and combination treatment. In addition, we observed that epistatic effects between gyrA and parC mutations strongly alter the strength of collateral effects against different antibiotics. Our model simulations, which included the experimentally derived antibiotic susceptibilities and fitness effects, and antibiotic specific pharmacodynamics, revealed that both collateral and fitness effects impact the population dynamics of resistance evolution. Overall, we provide evidence that the gene, mutational identity, and interactions between resistance mutations can have a pronounced impact on collateral effects to different antibiotics and suggest that these need to be considered in models examining CS-based therapies.

Design principles of collateral sensitivity-based dosing strategies

“…In the case where CS was only present for the first antibiotic (ABA) (Figure 5D), the initial bacterial growth was extensive, thus leading to increased risk of the double resistant subpopulation emerging. We consider this finding relevant because one-directional CS relationships are much more common than reciprocal CS relationships [9][10][11][12][13][14][15][16],…”

“…CS has been extensively characterized in vitro, typically by evolving AMR strains and then quantifying correlated changes in the sensitivity to other antibiotics [9][10][11][12]. CS effects have been characterized for several clinically relevant pathogens, including Escherichia coli [9,13], Pseudomonas aeruginosa [14], Enterococcus faecalis [13], Streptococcus pneumoniae [15], and Staphylococcus aureus [16]. CS relationships between antibiotics can either be one directional, where decreased sensitivity to one antibiotic show CS to a second antibiotic but not the reverse, or reciprocal, where decreased sensitivity either of the antibiotics results in CS to the other.…”

“…Experimental studies in vitro are essential to characterize the incidence, evolvability and magnitude of CS, all of which are important but isolated components that may contribute to the success of CS-based treatments [9][10][11][12][13][14][15][16]. However, for translation of in vitro CS findings to in vivo or clinical treatment scenarios, consideration of pharmacodynamic (PD) and pharmacokinetic (PK) factors is essential, as these determine the differential impact of different antibiotics on the rate and concentration dependent effects of bacterial growth, inhibition, and killing [17,18].…”

“…CS relationships between antibiotics can either be one directional, where decreased sensitivity to one antibiotic show CS to a second antibiotic but not the reverse, or reciprocal, where decreased sensitivity to either of the antibiotics results in CS to the other. Reciprocal CS is often considered a prerequisite for effective CS-based treatments, but such relationships have been less frequently observed compared to one directional CS [9][10][11][12][13][14][15][16] .…”

“…Experimental studies in vitro are essential to characterize the incidence, evolvability and magnitude of CS, all of which are important but isolated components that may contribute to the success of CS-based treatments [9][10][11][12][13][14][15][16] .…”