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Silk-Based Therapeutics Targeting Pseudomonas aeruginosa.

ABSTRACT: Pseudomonas aeruginosa (P. aeruginosa) infections may lead to severe damage of the cornea, mucosa, and skin. The highly aggressive nature of P. aeruginosa and the rise in multi-drug resistance, particularly in nosocomial settings, lead to an increased risk for permanent tissue damage and potentially death. Thus, a growing need exists to develop alternative treatments to reduce both the occurrence of bacterial infection and biofilm development, as well as pathological progression post-infection. Silk derived from Bombyx mori silkworms serves as a unique biomaterial that is biocompatible with low immunogenicity and high versatility, and thereby ideal for stabilizing therapeutics. In this study, we assessed the cytotoxicity of P. aeruginosa on human corneal stromal stem cells and two mucosal cell lines (Caco-2 and HT29-MTX). To determine whether antibiotic-immobilized scaffolds can serve as alternative therapeutics to free, diffuse forms, we developed novel gentamicin-conjugated silk films as functional scaffolds and compared antimicrobial effects and free gentamicin. The advantages of generating a surface coating with a covalently-bound antibiotic may reduce potential side-effects associated with free gentamicin, as well as limit the diffusion of the drug. Our results suggest that gentamicin conjugated to native silk and carboxyl-enriched silk inhibits P. aeruginosa growth. Development of stabilized antibiotic treatments with surface toxicity selective against bacteria may serve as an alternative approach to treat active infections, as well as potential prophylactic use as coatings in high-risk cases, such as post-surgical complications or prolonged hospitalization.

SUBMITTER: McKay TB

PROVIDER: S-EPMC6787730 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Silk-Based Therapeutics Targeting Pseudomonas aeruginosa.

McKay Tina B TB Parker Rachael N RN Hawker Morgan J MJ McGill Meghan M Kaplan David L DL

Journal of functional biomaterials 20190913 3

Pseudomonas aeruginosa (P. aeruginosa) infections may lead to severe damage of the cornea, mucosa, and skin. The highly aggressive nature of P. aeruginosa and the rise in multi-drug resistance, particularly in nosocomial settings, lead to an increased risk for permanent tissue damage and potentially death. Thus, a growing need exists to develop alternative treatments to reduce both the occurrence of bacterial infection and biofilm development, as well as pathological progres ...[more]

PMID: 31540233

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Project description:A worrisome trend in the study and treatment of infectious disease noted in recent years is the increase in multidrug resistant strains of bacteria concurrent with a scarcity of new antimicrobial agents to counteract this rise. This is particularly true amongst bacteria within the Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species (ESKAPE) designation. P. aeruginosa is one of the most common causes of bacterial keratitis. Therefore, it is of vital importance to characterize new antimicrobial agents with anti-Pseudomonal activity for use with the ocular surface. MEDI3902 is a multifunctional antibody that targets the P. aeruginosa persistence factor Psl exopolysaccharide, and the type 3 secretion protein PcrV. We initially assessed this antibody for ocular surface toxicity. The antimicrobial activity of the antibody was then tested by treating mice with established P. aeruginosa keratitis with both topical and intravenous treatment modalities. MEDI3902, was shown to be non-toxic to the ocular surface of mice when given topically. It was also effective compared to the control antibody at preventing P. aeruginosa keratitis with a one-time treatment at the time of infection. Both topical and intravenous administration of MEDI3902 has been proved significant in treating established keratitis infections as well, speeding the resolution of infection significantly more than that of the control IgG. We report the first use of a topical immunotherapeutic multifunctional agent targeting Psl and type 3 secretion on the ocular surface as an antimicrobial agent. While MEDI3902 has been shown to prevent Pseudomonas biofilm formation in keratitis models when given prophylactically intravitally, we show that MEDI3902 has the capability to also treat an active infection when given intravenously to mice with Pseudomonas keratitis. Our data indicate antibodies are well tolerated and nontoxic on the ocular surface. They reduce infection in mice treated concurrently at inoculation and reduced the signs of cornea pathology in mice with established infection. Taken together, these data indicate treatment with monoclonal antibodies directed against Psl and PcrV may be clinically effective in the treatment of P. aeruginosa keratitis and suggest that the design of further antibodies to be an additional tool in the treatment of bacterial keratitis.

Dataset Information

Silk-Based Therapeutics Targeting Pseudomonas aeruginosa.

Publications

Silk-Based Therapeutics Targeting <i>Pseudomonas aeruginosa</i>.

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