Pyocin efficacy in a murine model of<i>Pseudomonas aeruginosa</i>sepsis

Six, Anne; Mosbahi, Khédidja; Barge, Madhuri; Kleanthous, Colin; Evans, Thomas J.; Walker, Daniel

doi:10.1101/2020.03.27.011908

Cited by 6 publications

(6 citation statements)

References 25 publications

(29 reference statements)

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“…Colicin and bacteriophage intoxication: Colicins and bacteriophages typically associate with two components of the OM to activate import and infection, respectively, in E. coli . The long tail fibers of bacteriophage T4 bind LPS and OmpC ( 62 ), and colicin E9 binds OmpF and BtuB ( 35 , 42 ). In both cases, the two components are colocated by virtue of the lipid-mediated OMP network.…”

Section: Discussionmentioning

confidence: 99%

“…We first established the relative cellular distribution of our target OMPs using fluorescence imaging in E. coli MG1655 cells. OmpF, FepA, and BtuB were specifically labeled with fluorescently tagged, high-affinity colicins inactivated for toxicity (27,(33)(34)(35) and visualized by total internal reflection fluorescence microscopy (fig. S1, A and B).…”

Section: Strategy For Capturing Omp Near-neighbor Contacts In Live E ...mentioning

confidence: 99%

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Lipids mediate supramolecular outer membrane protein assembly in bacteria

et al. 2022

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β Barrel outer membrane proteins (OMPs) cluster into supramolecular assemblies that give function to the outer membrane (OM) of Gram-negative bacteria. How such assemblies form is unknown. Here, through photoactivatable cross-linking into the Escherichia coli OM, coupled with simulations, and biochemical and biophysical analysis, we uncover the basis for OMP clustering in vivo. OMPs are typically surrounded by an annular shell of asymmetric lipids that mediate higher-order complexes with neighboring OMPs. OMP assemblies center on the abundant porins OmpF and OmpC, against which low-abundance monomeric β barrels, such as TonB-dependent transporters, are packed. Our study reveals OMP-lipid-OMP complexes to be the basic unit of supramolecular OMP assembly that, by extending across the entire cell surface, couples the requisite multifunctionality of the OM to its stability and impermeability.

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Section: Discussionmentioning

confidence: 99%

Section: Strategy For Capturing Omp Near-neighbor Contacts In Live E ...mentioning

confidence: 99%

Lipids mediate supramolecular outer membrane protein assembly in bacteria

et al. 2022

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“…A recent study showed that colicins can be used to disrupt biofilm integrity [223]. Moreover, when injected into the bloodstream of mice, pyocin S5 was observed to retain its functionality and to improve mouse survival to Pseudomonas infections [224]. Another study demonstrated that microcapsule delivery of the active form of colicin Ia reduced E. coli colonisation in murine models [225].…”

Section: Discussionmentioning

confidence: 99%

Bacterial pore-forming toxins

Ulhuq

Mariano

2022

Microbiology

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Pore-forming toxins (PFTs) are widely distributed in both Gram-negative and Gram-positive bacteria. PFTs can act as virulence factors that bacteria utilise in dissemination and host colonisation or, alternatively, they can be employed to compete with rival microbes in polymicrobial niches. PFTs transition from a soluble form to become membrane-embedded by undergoing large conformational changes. Once inserted, they perforate the membrane, causing uncontrolled efflux of ions and/or nutrients and dissipating the protonmotive force (PMF). In some instances, target cells intoxicated by PFTs display additional effects as part of the cellular response to pore formation. Significant progress has been made in the mechanistic description of pore formation for the different PFTs families, but in several cases a complete understanding of pore structure remains lacking. PFTs have evolved recognition mechanisms to bind specific receptors that define their host tropism, although this can be remarkably diverse even within the same family. Here we summarise the salient features of PFTs and highlight where additional research is necessary to fully understand the mechanism of pore formation by members of this diverse group of protein toxins.

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“…Narrow-spectrum protein bacteriocins are emerging as promising alternative antibiotics and could be utilized to target specific pathogenic bacteria in the complex microbial community of the human microbiota, sparing the key eubiotic organisms ( Brown et al, 2015 ; McCaughey et al, 2016 ; Six et al, 2020 ). The best studied of the protein bacteriocins are the colicins, which specifically target E. coli and strains of other closely related bacterial species ( Cascales et al, 2007 ).…”

Section: Introductionmentioning

confidence: 99%

Targeted Delivery of Narrow-Spectrum Protein Antibiotics to the Lower Gastrointestinal Tract in a Murine Model of Escherichia coli Colonization

Carpena

Richards²,

González³

et al. 2021

Front. Microbiol.

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Bacteriocins are narrow-spectrum protein antibiotics that could potentially be used to engineer the human gut microbiota. However, technologies for targeted delivery of proteins to the lower gastrointestinal (GI) tract in preclinical animal models are currently lacking. In this work, we have developed methods for the microencapsulation of Escherichia coli targeting bacteriocins, colicin E9 and Ia, in a pH responsive formulation to allow their targeted delivery and controlled release in an in vivo murine model of E. coli colonization. Membrane emulsification was used to produce a water-in-oil emulsion with the water-soluble polymer subsequently cross-linked to produce hydrogel microcapsules. The microcapsule fabrication process allowed control of the size of the drug delivery system and a near 100% yield of the encapsulated therapeutic cargo. pH-triggered release of the encapsulated colicins was achieved using a widely available pH-responsive anionic copolymer in combination with alginate biopolymers. In vivo experiments using a murine E. coli intestinal colonization model demonstrated that oral delivery of the encapsulated colicins resulted in a significant decrease in intestinal colonization and reduction in E. coli shedding in the feces of the animals. Employing controlled release drug delivery systems such as that described here is essential to enable delivery of new protein therapeutics or other biological interventions for testing within small animal models of infection. Such approaches may have considerable value for the future development of strategies to engineer the human gut microbiota, which is central to health and disease.

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Pyocin efficacy in a murine model ofPseudomonas aeruginosasepsis

Cited by 6 publications

References 25 publications

Lipids mediate supramolecular outer membrane protein assembly in bacteria

Lipids mediate supramolecular outer membrane protein assembly in bacteria

Bacterial pore-forming toxins

Targeted Delivery of Narrow-Spectrum Protein Antibiotics to the Lower Gastrointestinal Tract in a Murine Model of Escherichia coli Colonization

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