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

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.

Metabolic pathways that permit Mycobacterium avium subsp. hominissuis to transition to different environments encountered within the host during infection

“…That finding agrees with the fact that the persistence state requires a suitable carbon and energy source (other than glucose) to maintain a low flux status through core metabolic pathways (Amato et al, 2014;Cabral et al, 2018). Furthermore, we have previously observed that the utilization of both short-chain fatty acid (SCFA) and glycerol by both planktonic and biofilm bacteria affects the susceptibility of M. avium to clinically used antibiotics in established biofilms (Silva et al, 2020). The results of the study demonstrate that glycerol and the SCFA are processed by M. avium in biofilms as an energy source, supporting M. avium growth in both biofilms but also in planktonic state (Silva et al, 2020).…”

The Short-chain Fatty Acid Propionic Acid Activates the Rcs Stress Response System Partially through Inhibition of d- Alanine Racemase

“…Strong support for propionic acid activating the Rcs system is its ability to activate three different Rcs-regulated promoters in the WT but not in an isogenic Rcs-deficient mutant. Due to its antimicrobial effects, propionic acid is commonly used as a food preservative ( 39 ) and topically to treat skin infections ( 56 ), and it may influence the susceptibility of bacteria to other antibiotics ( 57 , 58 ). However, the antimicrobial mechanism of action is not fully understood, and it has been hypothesized to be derived from intracellular acidification ( 39 ).…”

The short chain fatty acid propionic acid activates the Rcs stress response system partially through inhibition of D-alanine racemase

“…Strong support for propionic acid activating the Rcs system is its ability to activate three different Rcs-regulated promoters in the WT, but not an isogenic Rcs-deficient mutant. Due to its antimicrobial effects, propionic acid is commonly used as a food preservative (38), used topically to treat skin infections (51), and may affect antibiotic susceptibility (52, 53). However, the mechanism of action is not fully understood and is hypothesized to be derived from intracellular acidification (38).…”