Diverse Clinical Isolates of Mycobacterium tuberculosis Develop Macrophage-Induced Rifampin Tolerance

Adams, Kristin N.; Verma, Amit; Adikesavalu, Harresh; Singhal, Dinesh Kumar; Tripathy, Srikanth; Ranganathan, Uma Devi; Sherman, David R.; Urdahl, Kevin B.; Ramakrishnan, Lalita; Hernandez, Rafael E.

doi:10.1093/infdis/jiy710

Cited by 19 publications

(15 citation statements)

References 14 publications

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“…Due to the fact that intracellular pathogens develop persistence phenotypes within the host and cellular environmental stresses play significant role in this process [ 61 , 62 , 63 ], we examined MAH susceptibility to antibiotic treatment in combination with SCFA within macrophages. The treatment with both antibiotics was found to be more lethal in combination with SCFA, significantly inhibiting intracellular MAH104 growth within the host macrophages.…”

Section: Discussionmentioning

confidence: 99%

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

2020

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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.

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Section: Discussionmentioning

confidence: 99%

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

2020

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“…These conditionally-active compounds would be overlooked in other screens against extracellular bacteria. There is accumulating evidence that intracellular bacteria are both heterogenous and antibiotic tolerant ( Vijay et al, 2017 ; Adams et al, 2019 ; Mandal et al, 2019 ; Mishra et al, 2019 ; Nair et al, 2019 ), and this may be one reason why drug treatment to achieve sterilization takes >4 months. The inclusion of compounds which specifically target intracellular bacteria in a drug regiment could be one approach to shorten therapy.…”

Section: Discussionmentioning

confidence: 99%

Identification of Novel Chemical Scaffolds that Inhibit the Growth of Mycobacterium tuberculosis in Macrophages

et al. 2022

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Mycobacterium tuberculosis is an important global pathogen for which new drugs are urgently required. The ability of the organism to survive and multiply within macrophages may contribute to the lengthy treatment regimen with multiple drugs that are required to cure the infection. We screened the MyriaScreen II diversity library of 10,000 compounds to identify novel inhibitors of M. tuberculosis growth within macrophage-like cells using high content analysis. Hits were selected which inhibited the intramacrophage growth of M. tuberculosis without significant cytotoxicity to infected macrophages. We selected and prioritized compound series based on their biological and physicochemical properties and the novelty of the chemotypes. We identified five chemical classes of interest and conducted limited catalog structure-activity relationship studies to determine their tractability. We tested activity against intracellular and extracellular M. tuberculosis, as well as cytoxicity against murine RAW264.7 and human HepG2 cells. Benzene amide ethers, thiophene carboxamides and thienopyridines were only active against intracellular bacteria, whereas the phenylthiourea series was also active against extracellular bacteria. One member of a phenyl pyrazole series was moderately active against extracellular bacteria. We identified the benzene amide ethers as an interesting series for further work. These new compound classes serve as starting points for the development of novel drugs to target intracellular M. tuberculosis.

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“…A recent THP-1 macrophage infection study by Adams et al . ( 2019 ) demonstrated that macrophages induced increased persistence (i.e. higher levels of heterotolerance) to isoniazid in MTBC strains belonging to L1, L2, L3 and L4.…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, Adams et al . ( 2019 ) showed that macrophages also induced increased persistence to rifampicin in L1, L3 and L4 strains, but not in L2 Beijing strains. This study therefore suggests that the magnitude of persistence or heterotolerance is dependent on the bacterial genotype.…”

Section: Introductionmentioning

confidence: 99%

“…( 2011 ) showed that L2 Beijing strains exhibited higher levels of intra-macrophage growth than non-Beijing MTBC strains, and that this increased intra-macrophage growth was abrogated when the L2 Beijing strains were treated with bacterial efflux inhibitor verapamil (Adams et al . 2019 ). However, in contrast to many other bacteria where the role of efflux pumps in clinical AMR is well supported (Du et al .…”

Section: Introductionmentioning

confidence: 99%

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The within-host evolution of antimicrobial resistance in Mycobacterium tuberculosis

Castro

Borrell

Gagneux

2020

FEMS Microbiology Reviews

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Tuberculosis (TB) has been responsible for the greatest number of human deaths due to an infectious disease in general, and due to antimicrobial resistance (AMR) in particular. The etiological agents of human TB are a closely-related group of human-adapted bacteria that belong to the Mycobacterium tuberculosis complex (MTBC). Understanding how MTBC populations evolve within-host may allow for improved TB treatment and control strategies. In this review, we highlight recent works that have shed light on how AMR evolves in MTBC populations within individual patients. We discuss the role of heteroresistance in AMR evolution, and review the bacterial, patient and environmental factors that likely modulate the magnitude of heteroresistance within-host. We further highlight recent works on the dynamics of MTBC genetic diversity within-host, and discuss how spatial substructures in patients’ lungs, spatiotemporal heterogeneity in antimicrobial concentrations and phenotypic drug tolerance likely modulates the dynamics of MTBC genetic diversity in patients during treatment. We note the general characteristics that are shared between how the MTBC and other bacterial pathogens evolve in humans, and highlight the characteristics unique to the MTBC.

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Diverse Clinical Isolates of Mycobacterium tuberculosis Develop Macrophage-Induced Rifampin Tolerance

Abstract: Mycobacterium tuberculosis develops tolerance to multiple antibiotics when residing in host macrophages. We demonstrate that macrophage-induced tolerance to rifampin is common across major lineages of M. tuberculosis, except for Beijing-family lineage 2 strains.

Cited by 19 publications

References 14 publications

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

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

Identification of Novel Chemical Scaffolds that Inhibit the Growth of Mycobacterium tuberculosis in Macrophages

The within-host evolution of antimicrobial resistance in Mycobacterium tuberculosis

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