Modelling the synergistic effect of bacteriophage and antibiotics on bacteria: killers and drivers of resistance evolution
Modelling the synergistic effect of bacteriophage and antibiotics on bacteria: killers and drivers of resistance evolution
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模拟噬菌体和抗生素对细菌的协同效应：耐药性进化的杀手和驱动因素
DOI：
10.1101/2022.03.02.480504
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Leclerc Q
中科院分区：
文献类型：
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作者：
Leclerc Q
噬菌体（噬菌体）是细菌捕食者，还可以通过广义转导在细菌之间传播抗菌素耐药性 (AMR) 基因。噬菌体通常与抗生素一起存在于环境中，但它们对细菌的联合杀伤作用的证据是相互矛盾的，并且此类系统中转导的动态尚不清楚。在这里，我们结合体外数据和数学模型来确定噬菌体和抗生素协同作用以去除细菌或驱动 AMR 进化的条件。我们采用已发表的噬菌体-细菌动力学模型（包括转导）来添加红霉素和四环素的药效学，并根据新的体外数据进行参数化。我们模拟了一个系统，其中有两种金黄色葡萄球菌菌株处于稳定期，每种菌株都携带红霉素或四环素抗性基因，并且仅通过转导即可产生多重耐药细菌。当抗生素和噬菌体中的一种或两种以不同的时间和浓度存在时，我们确定细菌清除率和多重耐药细菌的出现率。尽管噬菌体和抗生素协同作用来杀死细菌，但抗生素通过减少细菌生长来减少噬菌体的产生。抗生素使用后不久引入的低浓度噬菌体无法复制并对细菌施加强大的杀灭压力，而是通过转导产生多重耐药细菌，然后由抗生素选择。当同时引入抗生素和噬菌体时，多重耐药细菌数量最高。噬菌体和抗生素之间的相互作用导致细菌清除速度较慢（如果在噬菌体之前添加抗生素）和较高的多重耐药性进化风险（如果在抗生素之前添加噬菌体）之间的权衡，而低浓度的噬菌体或抗生素会加剧这种情况。我们的结果形成了假设，以指导未来有关噬菌体对 AMR 进化的影响的实验和临床工作，特别是噬菌体治疗的研究，该研究应研究噬菌体和抗生素的不同时间和浓度。
Bacteriophage (phage) are bacterial predators that can also spread antimicrobial resistance (AMR) genes between bacteria by generalised transduction. Phage are often present alongside antibiotics in the environment, yet evidence of their joint killing effect on bacteria is conflicted, and the dynamics of transduction in such systems are unknown. Here, we combinein vitrodata and mathematical modelling to identify conditions where phage and antibiotics act in synergy to remove bacteria or drive AMR evolution. We adapt a published model of phage-bacteria dynamics, including transduction, to add the pharmacodynamics of erythromycin and tetracycline, parameterised from newin vitrodata. We simulate a system where two strains ofStaphylococcus aureusare present at stationary phase, each carrying either an erythromycin or tetracycline resistance gene, and where multidrug-resistant bacteria can be generated by transduction only. We determine rates of bacterial clearance and multidrug-resistant bacteria appearance, when either or both antibiotics and phage are present at varying timings and concentrations. Although phage and antibiotics act in synergy to kill bacteria, by reducing bacterial growth antibiotics reduce phage production. A low concentration of phage introduced shortly after antibiotics fails to replicate and exert a strong killing pressure on bacteria, instead generating multidrug-resistant bacteria by transduction which are then selected for by the antibiotics. Multidrug-resistant bacteria numbers were highest when antibiotics and phage were introduced simultaneously. The interaction between phage and antibiotics leads to a trade-off between a slower clearing rate of bacteria (if antibiotics are added before phage), and a higher risk of multidrug-resistance evolution (if phage are added before antibiotics), exacerbated by low concentrations of phage or antibiotics. Our results form hypotheses to guide future experimental and clinical work on the impact of phage on AMR evolution, notably for studies of phage therapy which should investigate varying timings and concentrations of phage and antibiotics.