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 Streptococcus pneumoniae by measuring collateral and fitness effects of clinically relevant gyrA and parC alleles, 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 alleles; however, the spectrum of collateral effects was unique for each allele or allelic pair. This indicated that allelic identity can impact the evolutionary dynamics of resistance evolution during monotreatment and combination treatment. 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 allelic identity and interactions 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.

中文翻译：

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等位基因特异性侧枝和适应度效应决定了氟喹诺酮耐药性进化的动力学

当对一种抗生素的耐药性增加对其他抗生素的敏感性时会出现侧支敏感性 (CS)，它提供了新的治疗机会来限制或逆转抗生素耐药性的演变。CS 知情治疗的适用性仍然不确定，部分原因是我们缺乏对 CS 对单独或组合的不同抗性突变的影响的普遍性的理解。在这里，我们通过测量临床相关的gyrA和parC等位基因及其组合的附带和健康效应来解决革兰氏阳性病原体肺炎链球菌中的这个问题，这些基因赋予对氟喹诺酮类药物的抗性。我们将这些结果整合到一个数学模型中，使我们能够评估不同in silico联合治疗会影响耐药性进化的动态。我们确定了不同gyrA和parC 的常见和保守的 CS 效应等位基因；然而，每个等位基因或等位基因对的附带效应谱是独一无二的。这表明等位基因同一性可以影响单一治疗和联合治疗期间抗性进化的进化动力学。我们的模型模拟，包括实验得出的抗生素敏感性和适应性效应，以及抗生素特异性药效学，揭示了附带效应和适应性效应都会影响耐药性进化的种群动态。总体而言，我们提供的证据表明等位基因同一性和相互作用可以对不同抗生素的附带效应产生显着影响，并建议在检查基于 CS 的疗法的模型中需要考虑这些。