Card Kyle J, Crozier Dena, Durmaz Arda, Gray Jason, Creary Justin, Stocks Amira, Maltas Jeff, Bonomo Robert A, Burke Zachary D C, Scott Jacob G
Department of Translational Hematology & Oncology Research, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44106.
Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44106.
bioRxiv. 2025 Apr 5:2023.11.30.569373. doi: 10.1101/2023.11.30.569373.
bacteremia is typically treated empirically with vancomycin, with therapy later tailored based on susceptibility results. However, these tests occur before vancomycin exposure and do not account for adaptation during empiric treatment that can alter ' susceptibility to first-line drugs. To investigate these collateral drug responses, we experimentally evolved 18 methicillin-susceptible (MSSA) populations under increasing vancomycin concentrations until they achieved intermediate resistance. Genomic sequencing revealed two distinct adaptive pathways characterized by mutations in the WalKR regulon, affecting cell wall metabolism, or , impacting translational stress responses. These pathways correlated with divergent collateral sensitivity profiles to first-line antibiotics. By developing a Collateral Response Score (CRS), we quantified the probability and magnitude of these responses, demonstrating that evolutionary dynamics critically influence resistance outcomes. Our findings suggest a probabilistic approach to antimicrobial therapy, advocating for rapid genomic diagnostics alongside susceptibility testing to better anticipate and respond to evolutionary changes.
菌血症通常经验性地用万古霉素治疗，随后根据药敏结果调整治疗方案。然而，这些检测在接触万古霉素之前进行，并未考虑经验性治疗期间可能改变对一线药物敏感性的适应性变化。为了研究这些间接药物反应，我们在不断增加的万古霉素浓度下对18个甲氧西林敏感（MSSA）群体进行了实验进化，直到它们获得中介耐药性。基因组测序揭示了两条不同的适应性途径，其特征是WalKR调节子发生突变，影响细胞壁代谢，或者影响翻译应激反应。这些途径与对一线抗生素的不同间接敏感性谱相关。通过开发间接反应评分（CRS），我们量化了这些反应的概率和幅度，表明进化动力学对耐药结果有至关重要的影响。我们的研究结果提出了一种抗菌治疗的概率方法，主张在药敏试验的同时进行快速基因组诊断，以更好地预测和应对进化变化。
