The outer-membrane protein TolC of Vibrio cholerae serves as a second cell-surface receptor for the VP3 phage

Fan, Fenxia; Xu, Li; Pang, Bo; Cheng, Zhenshun; Li, Zhe; Zhang, Lijuan; Li, Jie; Zhang, Jingyun; Yan, Mei; Liang, Weili; Kan, Biao

doi:10.1074/jbc.m117.805689

Cited by 21 publications

(16 citation statements)

References 76 publications

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“…It has been shown that phage TLS selects for tolC mutants that are hypersensitive to novobiocin (13). Moreover, TolC has been identified as a phage receptor in other Gram-negative pathogens (14,15), giving further support to the combined use of phage and antibiotics. Similarly, the phage OMKO1 may be able to use multiple binding targets to infect P. aeruginosa, including the type IV pilus and the multidrug efflux pump MexAB/MexXY (7); both mechanisms can result in selection against drug resistance.…”

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confidence: 99%

Quantitative Models of Phage-Antibiotic Combination Therapy

et al. 2020

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The spread of multidrug-resistant (MDR) bacteria is a global public health crisis. Bacteriophage therapy (or “phage therapy”) constitutes a potential alternative approach to treat MDR infections. However, the effective use of phage therapy may be limited when phage-resistant bacterial mutants evolve and proliferate during treatment. Here, we develop a nonlinear population dynamics model of combination therapy that accounts for the system-level interactions between bacteria, phage, and antibiotics for in vivo application given an immune response against bacteria. We simulate the combination therapy model for two strains of Pseudomonas aeruginosa, one which is phage sensitive (and antibiotic resistant) and one which is antibiotic sensitive (and phage resistant). We find that combination therapy outperforms either phage or antibiotic alone and that therapeutic effectiveness is enhanced given interaction with innate immune responses. Notably, therapeutic success can be achieved even at subinhibitory concentrations of antibiotics, e.g., ciprofloxacin. These in silico findings provide further support to the nascent application of combination therapy to treat MDR bacterial infections, while highlighting the role of innate immunity in shaping therapeutic outcomes. IMPORTANCE This work develops and analyzes a novel model of phage-antibiotic combination therapy, specifically adapted to an in vivo context. The objective is to explore the underlying basis for clinical application of combination therapy utilizing bacteriophage that target antibiotic efflux pumps in Pseudomonas aeruginosa. In doing so, the paper addresses three key questions. How robust is combination therapy to variation in the resistance profiles of pathogens? What is the role of immune responses in shaping therapeutic outcomes? What levels of phage and antibiotics are necessary for curative success? As we show, combination therapy outperforms either phage or antibiotic alone, and therapeutic effectiveness is enhanced given interaction with innate immune responses. Notably, therapeutic success can be achieved even at subinhibitory concentrations of antibiotic. These in silico findings provide further support to the nascent application of combination therapy to treat MDR bacterial infections, while highlighting the role of system-level feedbacks in shaping therapeutic outcomes.

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confidence: 99%

Quantitative Models of Phage-Antibiotic Combination Therapy

et al. 2020

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“…It has been shown that phage TLS selects for tolC mutants that are hypersensitive to novobiocin 13 . Moreover, TolC has been identified as a phage receptor in other Gram-negative pathogens 14,15 , giving further support to the combined use of phage and antibiotics. Similarly, the phage OMKO1 may be able to use multiple binding targets to infect P.a., including the type-IV pilus and the multidrug efflux pump, MexAB/MexXY 7 , both mechanisms can result in selection against drug resistance.…”

Section: Introductionmentioning

confidence: 88%

Quantitative Models of Phage-Antibiotics Combination Therapy

Rodriguez-Gonzalez

Leung

Turner

et al. 2019

Preprint

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The spread of multi-drug resistant (MDR) bacteria is a global public health crisis. Bacteriophage therapy (or "phage therapy") constitutes a potential alternative approach to treat MDR infections. However, the effective use of phage therapy may be limited when phage-resistant bacterial mutants evolve and proliferate during treatment. Here, we develop a nonlinear population dynamics model of combination therapy that accounts for the system-level interactions between bacteria, phage and antibiotics for in-vivo application given an immune response against bacteria. We simulate the combination therapy model for two strains of Pseudomonas aeruginosa, one which is phage-sensitive (and antibiotic resistant) and one which is antibiotic-sensitive (and phage-resistant). We find that combination therapy outperforms either phage or antibiotic alone, and that therapeutic effectiveness is enhanced given interaction with innate immune responses. Notably, therapeutic success can be achieved even at sub-inhibitory concentrations of antibiotics, e.g., ciprofloxacin. These in-silico findings provide further support to the nascent application of combination therapy to treat MDR bacterial infections, while highlighting the role of innate immunity in shaping therapeutic outcomes.

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“…For a bacterial two-hybrid assay, the recombinant plasmids pKT25- epsD and pUT18C-gp20 were constructed as previously described ( Fan et al., 2018 ). Briefly, two putative interacting proteins (EpsD and gp20) were genetically fused to two complementary fragments, T25 and T18, of the active domain of adenylate cyclase (CyaA) from Bordetella pertussis ( Ladant, 1988 ).…”

Section: Methodsmentioning

confidence: 99%

The Type II Secretory System Mediates Phage Infection in Vibrio cholerae

Sun

Liu

Fan

et al. 2021

Front. Cell. Infect. Microbiol.

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Attachment and specific binding to the receptor on the host cell surface is the first step in the process of bacteriophage infection. The lytic phage VP2 is used in phage subtyping of the Vibrio cholerae biotype El Tor of the O1 serogroup; however, its infection mechanism is poorly understood. In this study, we aimed to identify its receptor on V. cholerae. The outer membrane protein EpsD in the type II secretory system (T2SS) was found to be related to VP2-specific adsorption to V. cholerae, and the T2SS inner membrane protein EpsM had a role in successful VP2 infection, although it was not related to adsorption of VP2. The tail fiber protein gp20 of VP2 directly interacts with EpsD. Therefore, we found that in V. cholerae, in addition to the roles of the T2SS as the transport apparatus of cholera toxin secretion and filamentous phage release, the T2SS is also used as the receptor for phage infection and probably as the channel for phage DNA injection. Our study expands the understanding of the roles of the T2SS in bacteria.

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The outer-membrane protein TolC of Vibrio cholerae serves as a second cell-surface receptor for the VP3 phage

Cited by 21 publications

References 76 publications

Quantitative Models of Phage-Antibiotic Combination Therapy

Quantitative Models of Phage-Antibiotic Combination Therapy

Quantitative Models of Phage-Antibiotics Combination Therapy

The Type II Secretory System Mediates Phage Infection in Vibrio cholerae

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