Filamentous Bacteriophages and the Competitive Interaction between Pseudomonas aeruginosa Strains under Antibiotic Treatment: a Modeling Study.
Filamentous Bacteriophages and the Competitive Interaction between Pseudomonas aeruginosa Strains under Antibiotic Treatment: a Modeling Study.
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DOI：
10.1128/msystems.00193-21
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发表时间：
2021-06-29
期刊：
影响因子：
6.4
通讯作者：
Bollyky PL
中科院分区：
文献类型：
--
作者：
Pourtois JD;Kratochvil MJ;Chen Q;Haddock NL;Burgener EB;De Leo GA;Bollyky PL
铜绿假单胞菌（Pa）是囊性纤维化患者慢性肺部感染的主要细菌病原体。最近的研究表明，由Pa产生的非溶性丝状病毒Pf噬菌体与Pa感染的慢性和严重程度有关。Pf噬菌体作为Pa生物膜的结构元件，隔离雾化抗生素，从而促进抗生素耐受性。与这种情况下的选择优势一致，这些患者中Pf阳性（Pf+）细菌的患病率随着时间的推移而增加。然而，Pf噬菌体的产生是以细菌的代谢成本为代价的，因此Pf+菌株比Pf-阴性（Pf−）菌株在体外生长得更慢。在这里，我们使用一个数学模型来研究这些竞争压力如何影响不同环境下Pf+与Pf -菌株的相对丰度。我们的模型表明，如果在大多数参数组合中，噬菌体生产的好处都落在Pf+和Pf -菌株上，那么Pf+菌株就不能胜过Pf -菌株。此外，噬菌体的产生仅在抗生素浓度略高于MIC（即，抗生素隔离的好处超过噬菌体产生的代谢成本的浓度）时才会导致适应度的净正增益，但对Pf+菌株不是致命的。因此，我们的模型表明，经常使用低腐烂率和高杀伤率的中等剂量抗生素有利于Pf+菌株而不是Pf−菌株。这些模型使我们了解了Pf噬菌体的生态学，并为Pf+ Pa感染提供了潜在的治疗策略。丝状噬菌体是细菌发病机制的前沿，但这些噬菌体对细菌适应性的影响尚不清楚。特别是，由Pa产生的Pf噬菌体促进抗生素耐受性，但其代谢成本很高，这表明竞争压力可能影响不同环境下Pa的Pf+菌株和Pf -菌株的流行。我们的结果确定条件可能有利于Pf+菌株，因此抗生素耐受性。这项研究有助于更好地了解丝状噬菌体在环境和临床环境中的独特生态，并可能促进改进治疗策略，以对抗抗生素耐药性。
Pseudomonas aeruginosa (Pa) is a major bacterial pathogen responsible for chronic lung infections in cystic fibrosis patients. Recent work has implicated Pf bacteriophages, nonlytic filamentous viruses produced by Pa, in the chronicity and severity of Pa infections. Pf phages act as structural elements in Pa biofilms and sequester aerosolized antibiotics, thereby contributing to antibiotic tolerance. Consistent with a selective advantage in this setting, the prevalence of Pf-positive (Pf+) bacteria increases over time in these patients. However, the production of Pf phages comes at a metabolic cost to bacteria, such that Pf+ strains grow more slowly than Pf-negative (Pf−) strains in vitro. Here, we use a mathematical model to investigate how these competing pressures might influence the relative abundance of Pf+ versus Pf− strains in different settings. Our model suggests that Pf+ strains of Pa cannot outcompete Pf− strains if the benefits of phage production falls onto both Pf+ and Pf− strains for a majority of parameter combinations. Further, phage production leads to a net positive gain in fitness only at antibiotic concentrations slightly above the MIC (i.e., concentrations for which the benefits of antibiotic sequestration outweigh the metabolic cost of phage production) but which are not lethal for Pf+ strains. As a result, our model suggests that frequent administration of intermediate doses of antibiotics with low decay rates and high killing rates favors Pf+ over Pf− strains. These models inform our understanding of the ecology of Pf phages and suggest potential treatment strategies for Pf+ Pa infections. IMPORTANCE Filamentous phages are a frontier in bacterial pathogenesis, but the impact of these phages on bacterial fitness is unclear. In particular, Pf phages produced by Pa promote antibiotic tolerance but are metabolically expensive to produce, suggesting that competing pressures may influence the prevalence of Pf+ versus Pf− strains of Pa in different settings. Our results identify conditions likely to favor Pf+ strains and thus antibiotic tolerance. This study contributes to a better understanding of the unique ecology of filamentous phages in both environmental and clinical settings and may facilitate improved treatment strategies for combating antibiotic tolerance.