Cysteamine, an Endogenous Aminothiol, and Cystamine, the Disulfide Product of Oxidation, Increase Pseudomonas aeruginosa Sensitivity to Reactive Oxygen and Nitrogen Species and Potentiate Therapeutic Antibiotics against Bacterial Infection.

Douglas J Fraser-Pitt,Derry K Mercer,Robert L R Hill,Michel Doumith,Deborah A O'Neil,Peter Perenyi,Aleksandra Kowalczuk,Daniel Smith,Katie L Hopkins,Neil Woodford,Michelle Cole,Emma Lovie,Jennifer Robertson,Andreas J Bäumler

doi:10.1128/iai.00947-17

Douglas J Fraser-Pitt, Derry K Mercer + Show 12 more

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https://doi.org/10.1128/iai.00947-17

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Abstract

ABSTRACTCysteamine is an endogenous aminothiol produced in mammalian cells as a consequence of coenzyme A metabolism through the activity of the vanin family of pantetheinase ectoenzymes. It is known to have a biological role in oxidative stress, inflammation, and cell migration. There have been several reports demonstrating anti-infective properties targeting viruses, bacteria, and even the malarial parasite. We and others have previously described broad-spectrum antimicrobial and antibiofilm activities of cysteamine. Here, we go further to demonstrate redox-dependent mechanisms of action for the compound and how its antimicrobial effects are, at least in part, due to undermining bacterial defenses against oxidative and nitrosative challenges. We demonstrate the therapeutic potentiation of antibiotic therapy against Pseudomonas aeruginosa in mouse models of infection. We also demonstrate potentiation of many different classes of antibiotics against a selection of priority antibiotic-resistant pathogens, including colistin (often considered an antibiotic of last resort), and we discuss how this endogenous antimicrobial component of innate immunity has a role in infectious disease that is beginning to be explored and is not yet fully understood.

Highlights

Cysteamine is an endogenous aminothiol produced in mammalian cells as a consequence of coenzyme A metabolism through the activity of the vanin family of pantetheinase ectoenzymes
We and others have previously demonstrated that CYS has antimicrobial properties against bacteria associated with cystic fibrosis (CF) respiratory tract infections, including Pseudomonas aeruginosa, Mycobacterium abscessus, and the Burkholderia cepacia complex (BCC)
We report here that exposure to CYS in a pro-oxidative environment, or to the oxidized disulfide CTM itself, dysregulates bacterial metabolism and reduces the capacity of P. aeruginosa to resist oxidative and nitrosative stress elicited by exogenous sources

Summary

Introduction

Cysteamine is an endogenous aminothiol produced in mammalian cells as a consequence of coenzyme A metabolism through the activity of the vanin family of pantetheinase ectoenzymes. In a reducing environment in the absence of transition metals, CYS can act as an antioxidant, so its activity is highly dependent upon the physiological context It will readily form mixed disulfides with susceptible cysteine sulfhydryl groups in a process called cysteaminylation [3], which is key for many reported biological activities. The oxidized disulfide CTM has been shown to possess antiretroviral properties against HIV [21], and endogenously produced CYS was recently shown to limit influenza virus replication in A549 cells [22]. It is being studied as an adjunct to antimalarial therapy [23, 24]. CYS impairs bacterial virulence at subinhibitory levels, with striking effects on bacterial pigment production, including phenazines in P. aeruginosa and pyomelanin in BCC

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