Rational design of a hospital-specific phage cocktail to treat Enterobacter cloacae complex infections.

IF 19.4 1区生物学 Q1 MICROBIOLOGY

Nature Microbiology Pub Date : 2025-09-24 DOI:10.1038/s41564-025-02130-4

Dinesh Subedi,Fernando Gordillo Altamirano,Rylee Deehan,Avindya Perera,Ruzeen Patwa,Xenia Kostoulias,Denis Korneev,Luke Blakeway,Nenad Macesic,Anton Y Peleg,Jeremy J Barr

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Abstract

The Alfred Hospital in Melbourne, Australia, has reported an ongoing outbreak of infections caused by multidrug-resistant Enterobacter cloacae complex (ECC). Phage therapy is a promising strategy to treat antimicrobial-resistant infections. Utilizing the hospital's isolate collection, built over the past decade, we established an initial 3-phage cocktail with 54% ECC coverage. We then iteratively improved this product by enhancing phage killing efficiency using phage adaptation and expanded host range through targeted phage isolation against low-coverage ECC isolates. This optimization yielded Entelli-02, containing five well-characterized virulent phages that target clinical ECC isolates via distinct bacterial cell surface receptors. Entelli-02 exhibits 88% host coverage against The Alfred Hospital's ECC isolate collection (n = 206), confirmed by plaque formation and reduced bacterial load in septicaemic mice by >99%. We produced this cocktail as a therapeutic-grade product, ready for clinical use. Entelli-02 represents a hospital-specific phage cocktail with frontline efficacy and on-demand availability.

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医院特异性噬菌体鸡尾酒治疗阴沟肠杆菌复合感染的合理设计。

澳大利亚墨尔本阿尔弗雷德医院报告了一起由耐多药阴沟肠杆菌复合体（ECC）引起的持续暴发感染。噬菌体治疗是治疗抗微生物耐药性感染的一种很有前途的策略。利用医院过去十年建立的隔离收集，我们建立了一种初始的3噬菌体鸡尾酒，ECC覆盖率为54%。然后，我们通过噬菌体适应性提高噬菌体杀灭效率，并通过靶向噬菌体分离来扩大宿主范围，以对抗低覆盖率的ECC分离物，反复改进该产品。这种优化得到了Entelli-02，包含五种具有良好特征的强毒噬菌体，通过不同的细菌细胞表面受体靶向临床ECC分离株。Entelli-02对Alfred医院的ECC分离物（n = 206）具有88%的宿主覆盖率，通过菌斑形成和败血症小鼠的细菌负荷减少bbbb99 %证实了这一点。我们生产这种鸡尾酒作为治疗级产品，准备临床使用。Entelli-02是一种医院特异性噬菌体鸡尾酒，具有一线疗效和按需供应。

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来源期刊

Nature Microbiology Immunology and Microbiology-Microbiology

CiteScore

44.40

自引率

1.10%

发文量

226

期刊介绍： Nature Microbiology aims to cover a comprehensive range of topics related to microorganisms. This includes: Evolution: The journal is interested in exploring the evolutionary aspects of microorganisms. This may include research on their genetic diversity, adaptation, and speciation over time. Physiology and cell biology: Nature Microbiology seeks to understand the functions and characteristics of microorganisms at the cellular and physiological levels. This may involve studying their metabolism, growth patterns, and cellular processes. Interactions: The journal focuses on the interactions microorganisms have with each other, as well as their interactions with hosts or the environment. This encompasses investigations into microbial communities, symbiotic relationships, and microbial responses to different environments. Societal significance: Nature Microbiology recognizes the societal impact of microorganisms and welcomes studies that explore their practical applications. This may include research on microbial diseases, biotechnology, or environmental remediation. In summary, Nature Microbiology is interested in research related to the evolution, physiology and cell biology of microorganisms, their interactions, and their societal relevance.