Therapeutic potential of novel phages with antibiotic combinations against ESBL-producing and carbapenem-resistant Escherichia Coli

Abstract

• Isolated phages EC.W1–9 and EC.W15–4 are safe candidates for therapeutic use against multidrug-resistant (MDR) E. coli , lacking harmful genetic traits. • The combination of phages achieves a lysis rate of 61.7%, surpassing individual phage effectiveness against ESBL-producing and CREC isolates. • The phage combination demonstrates 100% susceptibility to multiple E. coli sequence types, highlighting its potential against diverse ESBL-producing and CREC isolates. • Combined phage and antibiotic treatment significantly improve survival rates in infected mice, presenting a promising strategy for managing severe infections. The emergence of extended-spectrum β -lactamase (ESBL)-producing E. coli and carbapenem-resistant E. coli (CREC) is a significant global health challenge. This study focuses on isolating and characterizing two novel phages, EC.W1–9 and EC.W15–4, and investigating their efficacy with antibiotics against these resistant E. coli . In vivo experiments were conducted using BALB/c mice, and E.coli isolates were collected, cultured, and evaluated for antibiotic susceptibility. Phages were isolated from hospital sewage and prepared to infect the E. coli . The isolated phages, EC.W1–9 and EC.W15–4, belonged to the Podoviridae and Straboviridae families, and lack integrase or toxin-coding genes, indicating safety for therapeutic use. The combination of these phages significently enhanced their lytic ability, lysing 61.7% of 60 E. coli isolates, compared to 41.6%–55% lysis by individual phages. Furthermore, the phage combination demonstrated 100% susceptibility against different E. coli sequence types, including ST73, ST648, ST2311, ST405, ST7962, ST131, ST13003, and ST167. Additionally, synergy between antibiotics and phage combinations improved susceptibility rates to 73.3% for ESBL producers and 54% for CREC. The combined treatment of isolated phages and antibiotics significantly increased survival rates in BALB/c mice exposed to resistant STs of E.coli , including ST131, ST648, and ST410. Survival rates against ST131 increased by approximately 75% and 50% compared to treatment individual phages. Combined treatment with two phages and antibiotics resulted in 75–100% survival against E. coli ST410 and 100% survival against ST648 This study highlights the therapeutic importance of phage and phage-antibiotic combinations in combating ESBL-producing E. coli and CREC isolates.

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