Institute of Food Nutrition and Health, ETH Zurich, Zurich, Switzerland.
Department of Neuro-Urology, Balgrist University Hospital, University of Zurich, Zurich, Switzerland.
Nat Commun. 2023 Jul 20;14(1):4337. doi: 10.1038/s41467-023-39612-0.
Bacteriophages operate via pathogen-specific mechanisms of action distinct from conventional, broad-spectrum antibiotics and are emerging as promising alternative antimicrobials. However, phage-mediated killing is often limited by bacterial resistance development. Here, we engineer phages for target-specific effector gene delivery and host-dependent production of colicin-like bacteriocins and cell wall hydrolases. Using urinary tract infection (UTI) as a model, we show how heterologous effector phage therapeutics (HEPTs) suppress resistance and improve uropathogen killing by dual phage- and effector-mediated targeting. Moreover, we designed HEPTs to control polymicrobial uropathogen communities through production of effectors with cross-genus activity. Using phage-based companion diagnostics, we identified potential HEPT responder patients and treated their urine ex vivo. Compared to wildtype phage, a colicin E7-producing HEPT demonstrated superior control of patient E. coli bacteriuria. Arming phages with heterologous effectors paves the way for successful UTI treatment and represents a versatile tool to enhance and adapt phage-based precision antimicrobials.
噬菌体通过不同于传统广谱抗生素的特定病原体作用机制发挥作用，正在成为有前途的替代抗菌药物。然而，噬菌体介导的杀伤作用常常受到细菌耐药性发展的限制。在这里，我们设计了针对特定靶点的噬菌体，用于效应基因的靶向传递，并在宿主依赖性条件下产生类 colicin 细菌素和细胞壁水解酶。我们以尿路感染 (UTI) 为模型，展示了异源效应噬菌体治疗剂 (HEPT) 如何通过双重噬菌体和效应物靶向来抑制耐药性并提高尿路病原体的杀伤效果。此外，我们设计了 HEPTs，通过产生具有跨属活性的效应物来控制多微生物尿路病原体群落。我们使用基于噬菌体的伴随诊断，鉴定出潜在的 HEPT 响应患者，并对其尿液进行了离体治疗。与野生型噬菌体相比，产生 colicin E7 的 HEPT 对患者大肠杆菌菌尿症的控制效果更好。用异源效应器武装噬菌体为成功治疗尿路感染铺平了道路，代表了增强和适应基于噬菌体的精准抗菌药物的多功能工具。
