Short-Chain Fatty Acids Promote Mycobacterium avium subsp. hominissuis Growth in Nutrient-Limited Environments and Influence Susceptibility to Antibiotics.

Carlos Adriano De Matos E Silva,Rajoana Rojony,Lia Danelishvili,Luiz E Bermudez

doi:10.3390/pathogens9090700

Carlos Adriano De Matos E Silva, Rajoana Rojony + Show 2 more

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https://doi.org/10.3390/pathogens9090700

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Journal: Pathogens	Publication Date: Aug 26, 2020
Citations: 9	License type: CC BY 4.0

Affiliation: Oregon State University

Abstract

Mycobacterium avium subsp. hominissuis (MAH) is a common intracellular pathogen that infects immunocompromised individuals and patients with pre-existing chronic lung diseases, such as cystic fibrosis, who develop chronic and persistent pulmonary infections. The metabolic remodeling of MAH in response to host environmental stresses or within biofilms formed in bronchial airways plays an important role in development of the persistence phenotype contributing to the pathogen’s tolerance to antibiotic treatment. Recent studies suggest a direct relationship between bacterial metabolic state and antimicrobial susceptibility, and improved antibiotic efficacy has been associated with the enhanced metabolism in bacteria. In the current study, we tested approximately 200 exogenous carbon source-dependent metabolites and identified short-chain fatty acid (SCFA) substrates (propionic, butyric and caproic acids) that MAH can utilize in different physiological states. Selected SCFA enhanced MAH metabolic activity in planktonic and sessile states as well as in the static and established biofilms during nutrient-limited condition. The increased bacterial growth was observed in all conditions except in established biofilms. We also evaluated the influence of SCFA on MAH susceptibility to clinically used antibiotics in established biofilms and during infection of macrophages and found significant reduction in viable bacterial counts in vitro and in cultured macrophages, suggesting improved antibiotic effectiveness against persistent forms of MAH.

Highlights

Mycobacterium avium subsp. hominissuis (MAH) is an opportunistic pathogen of the nontuberculous (NTM) group that mainly affects individuals with underlying respiratory disorders or with immunosuppressed conditions [1,2,3,4]
Since it is well known that intracellular environment of the macrophage enhances the development of the drug-tolerance phenotype in mycobacteria [15,31], we evaluated MAH104 killing by antibiotics in cultured THP-1 human macrophages that were supplemented with glycerol or short-chain fatty acid (SCFA)
This tolerance state of the pathogen directly influences the effectiveness of antibiotics in vivo, subsequently, causing chronic MAH infections [49]

Summary

Introduction

Mycobacterium avium subsp. hominissuis (MAH) is an opportunistic pathogen of the nontuberculous (NTM) group that mainly affects individuals with underlying respiratory disorders (e.g., cystic fibrosis, emphysema) or with immunosuppressed conditions [1,2,3,4]. The therapeutic options for NTM patients are limited [6,7], and the prolonged antibiotic regimens required for MAH treatment can predispose the pathogen for the development of acquired drug-resistance [8]. An important challenge in the treatment of MAH infections is the pathogen’s ability to form biofilm in the lung airways. The metabolic remodeling that MAH undergo within biofilms is associated with the persistence phenotype and bacterial tolerance to antibiotic treatment [11,15,16]. The presence of persister cells within biofilms results in treatment relapse as well as it enhances the development of chronic NTM infections [17]

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