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<p>The increasing prevalence of extended-spectrum β-lactamase (ESBL)-producing <i>Escherichia coli</i> has significantly reduced the effectiveness of β-lactam antibiotics, necessitating alternative or adjunct antimicrobial strategies. Here, we report the isolation and comprehensive characterization of a novel lytic bacteriophage, Eco-MTCMU-01, targeting ESBL-producing <i>E. coli</i>. The phage was isolated from wastewater in Thailand and morphologically classified by transmission electron microscopy as a member of the Autographiviridae, exhibiting an icosahedral capsid and short tail. A complete genome was resolved using hybrid assembly of short- and long-read sequencing data, enabling robust phylogenomic assignment to the genus Vectrevirus. Comparative genomic analysis indicated that Eco-MTCMU-01 shares core genomic architecture with Vectrevirus members but lacks identifiable genes associated with lysogeny, antimicrobial resistance, virulence factors, or anti-CRISPR systems, supporting a strictly lytic lifestyle and favorable safety profile. Host range analysis demonstrated that Eco-MTCMU-01 exhibits a highly specific lytic spectrum, infecting <i>E. coli</i> ATCC 25,922 and a subset of clinical isolates, including ESBL-producing strains, while showing no activity against other tested Gram-negative or Gram-positive species. Functionally, although phage treatment alone did not achieve complete bacterial eradication after 24&#xa0;h, combination therapy with cefepime resulted in marked synergistic effects. Checkerboard assays yielded a fractional inhibitory concentration index (FICI) of 0.25, indicating strong synergy, and reduced the minimum inhibitory and bactericidal concentrations of cefepime from 32 to 64&#xa0;µg/mL to &lt; 8&#xa0;µg/mL against a representative ESBL-producing isolate. Collectively, Eco-MTCMU-01 represents a genomically well-characterized lytic phage with selective activity against clinically relevant <i>E. coli</i> and demonstrated capacity to enhance cefepime efficacy. These findings support further investigation of phage–antibiotic combination strategies and highlight the importance of integrating genomic safety assessment with quantitative functional validation in the development of phage therapeutics against antimicrobial-resistant pathogens.</p>

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Comparative genomics and cefepime synergy of a lytic Vectrevirus phage Eco-MTCMU-01, targeting extended spectrum β-lactamase-producing Escherichia coli

  • 期刊论文

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  • 发表日期：

    2026年7月3日

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  • Krit Thirapanmethee,
  • Made Rai Dwitya Wiradiputra,
  • Thanyarak Pholthong,
  • Nichapatr Vetboocha,
  • Paul R. Jaschke,
  • Mullika Traidej Chomnawang

摘要

The increasing prevalence of extended-spectrum β-lactamase (ESBL)-producing Escherichia coli has significantly reduced the effectiveness of β-lactam antibiotics, necessitating alternative or adjunct antimicrobial strategies. Here, we report the isolation and comprehensive characterization of a novel lytic bacteriophage, Eco-MTCMU-01, targeting ESBL-producing E. coli. The phage was isolated from wastewater in Thailand and morphologically classified by transmission electron microscopy as a member of the Autographiviridae, exhibiting an icosahedral capsid and short tail. A complete genome was resolved using hybrid assembly of short- and long-read sequencing data, enabling robust phylogenomic assignment to the genus Vectrevirus. Comparative genomic analysis indicated that Eco-MTCMU-01 shares core genomic architecture with Vectrevirus members but lacks identifiable genes associated with lysogeny, antimicrobial resistance, virulence factors, or anti-CRISPR systems, supporting a strictly lytic lifestyle and favorable safety profile. Host range analysis demonstrated that Eco-MTCMU-01 exhibits a highly specific lytic spectrum, infecting E. coli ATCC 25,922 and a subset of clinical isolates, including ESBL-producing strains, while showing no activity against other tested Gram-negative or Gram-positive species. Functionally, although phage treatment alone did not achieve complete bacterial eradication after 24 h, combination therapy with cefepime resulted in marked synergistic effects. Checkerboard assays yielded a fractional inhibitory concentration index (FICI) of 0.25, indicating strong synergy, and reduced the minimum inhibitory and bactericidal concentrations of cefepime from 32 to 64 µg/mL to < 8 µg/mL against a representative ESBL-producing isolate. Collectively, Eco-MTCMU-01 represents a genomically well-characterized lytic phage with selective activity against clinically relevant E. coli and demonstrated capacity to enhance cefepime efficacy. These findings support further investigation of phage–antibiotic combination strategies and highlight the importance of integrating genomic safety assessment with quantitative functional validation in the development of phage therapeutics against antimicrobial-resistant pathogens.