The continued rise in antibiotic resistance is precipitating a medical crisis. Bacteriophage (phage) has been hailed as one possible therapeutic option to augment the efficacy of antibiotics. However, only a few studies have addressed the synergistic relationship between phage and antibiotics. Here, we report a comprehensive analysis of phage-antibiotic interaction that evaluates synergism, additivism, and antagonism for all classes of antibiotics across clinically achievable stoichiometries. We combined an optically based real-time microtiter plate readout with a matrix-like heat map of treatment potencies to measure phage and antibiotic synergy (PAS), a process we term synography. Phage-antibiotic synography was performed against a pandemic drug-resistant clonal group of extraintestinal pathogenic Escherichia coli (ExPEC) with antibiotic levels blanketing the MIC across seven orders of viral titers. Our results suggest that, under certain conditions, phages provide an adjuvating effect by lowering the MIC for drug-resistant strains. Furthermore, synergistic and antagonistic interactions are highly dependent on the mechanism of bacterial inhibition by the class of antibiotic paired to the phage, and when synergism is observed, it suppresses the emergence of resistant cells. Host conditions that simulate the infection environment, including serum and urine, suppress PAS in a bacterial growth-dependent manner. Lastly, two different related phages that differed in their burst sizes produced drastically different synograms. Collectively, these data suggest lytic phages can resuscitate an ineffective antibiotic for previously resistant bacteria while also synergizing with antibiotics in a class-dependent manner, processes that may be dampened by lower bacterial growth rates found in host environments.

中文翻译：

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噬菌体-抗生素协同作用是由抗菌作用机制和化学计量的独特组合驱动的。


抗生素耐药性的持续上升正在加剧医疗危机。噬菌体（噬菌体）被誉为增强抗生素功效的一种可能的治疗选择。然而，只有少数研究探讨了噬菌体和抗生素之间的协同关系。在这里，我们报告了噬菌体-抗生素相互作用的综合分析，评估了临床可实现的化学计量中所有类别抗生素的协同作用、加成作用和拮抗作用。我们将基于光学的实时微量滴定板读数与治疗效力的矩阵式热图相结合，以测量噬菌体和抗生素的协同作用（PAS），我们将这一过程称为同义词学。针对肠外致病性大肠杆菌(ExPEC) 的大流行耐药克隆组进行了噬菌体-抗生素同谱分析，抗生素水平覆盖了 7 个病毒滴度的 MIC。我们的结果表明，在某些条件下，噬菌体通过降低耐药菌株的 MIC 来提供佐剂作用。此外，协同和拮抗相互作用高度依赖于与噬菌体配对的抗生素类别的细菌抑制机制，并且当观察到协同作用时，它会抑制耐药细胞的出现。模拟感染环境的宿主条件（包括血清和尿液）以细菌生长依赖性方式抑制 PAS。最后，两种不同的相关噬菌体的爆发大小不同，产生了截然不同的同义词。 总的来说，这些数据表明，裂解噬菌体可以使先前耐药的细菌复活无效的抗生素，同时还以类别依赖性方式与抗生素产生协同作用，这一过程可能会因宿主环境中细菌生长速度较低而受到抑制。