ArticlePloS one2009
A novel in vitro multiple-stress dormancy model for Mycobacterium tuberculosis generates a lipid-loaded, drug-tolerant, dormant pathogen.
Article in PloS one, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 237 papers.
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Who cites it
237 citing papers in PubMed.
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- Proteomic insights into a M. tuberculosis clinical isolate with an increased propensity to form viable but non-replicating subpopulations during acid stress.Scientific reports · 2026Article
- Exploring the Protein Landscape of Dormant Mycobacterium tuberculosis Through In Vitro Functional Studies.Advances in experimental medicine and biology · 2026Review
- PPARγ mediated enhanced lipid biogenesis fuelseLife · 2025Article
- Essential redundancies fuel Mycobacterium tuberculosis adaptation to the host.PLoS pathogens · 2025Review
- Deconvoluting drug interactions usingAntimicrobial agents and chemotherapy · 2025Article
- A viable but nonculturable state ofJournal of medical microbiology · 2025Article
- Incorporation of macrophage immune stresses into an intracellular assay of drug tolerance inAntimicrobial agents and chemotherapy · 2025Article
- TheeLife · 2025Article
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- Proteomic characterization ofmSystems · 2025Article
- How macrophage heterogeneity affects tuberculosis disease and therapy.Nature reviews. Immunology · 2025Review
- A proteomic and functional view of intrabacterial lipid inclusion biogenesis in mycobacteria.mBio · 2025Article
- Emergence of antibiotic-specificAntimicrobial agents and chemotherapy · 2025Article
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- Expression of Resuscitation-Promoting Factor C Stimulates the Growth ofInternational journal of microbiology · 2025Article
- Model systems to studyFrontiers in cellular and infection microbiology · 2025Review
- Can lipid body-positive rates ofFrontiers in immunology · 2025Article
177 more citing papers are in PubMed but not listed here.
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9 authors.
Funding
Abstract
backgroundMycobacterium tuberculosis (Mtb) becomes dormant and phenotypically drug resistant when it encounters multiple stresses within the host. Inability of currently available drugs to kill latent Mtb is a major impediment to curing and possibly eradicating tuberculosis (TB). Most in vitro dormancy models, using single stress factors, fail to generate a truly dormant Mtb population. An in vitro model that generates truly dormant Mtb cells is needed to elucidate the metabolic requirements that allow Mtb to successfully go through dormancy, identify new drug targets, and to screen drug candidates to discover novel drugs that can kill dormant pathogen. METHODOLOGY/PRINCIPAL
findingsWe developed a novel in vitro multiple-stress dormancy model for Mtb by applying combined stresses of low oxygen (5%), high CO(2) (10%), low nutrient (10% Dubos medium) and acidic pH (5.0), conditions Mtb is thought to encounter in the host. Under this condition, Mtb stopped replicating, lost acid-fastness, accumulated triacylglycerol (TG) and wax ester (WE), and concomitantly acquired phenotypic antibiotic-resistance. Putative neutral lipid biosynthetic genes were up-regulated. These genes may serve as potential targets for new antilatency drugs. The triacylglycerol synthase1 (tgs1) deletion mutant, with impaired ability to accumulate TG, exhibited a lesser degree of antibiotic tolerance and complementation restored antibiotic tolerance. Transcriptome analysis with microarray revealed the achievement of dormant state showing repression of energy generation, transcription and translation machineries and induction of stress-responsive genes. We adapted this model for drug screening using the Alamar Blue dye to quantify the antibiotic tolerant dormant cells. CONCLUSIONS/SIGNIFICANCE: The new in vitro multiple stress dormancy model efficiently generates Mtb cells meeting all criteria of dormancy, and this method is adaptable to high-throughput screening for drugs that can kill dormant Mtb. A critical link between storage-lipid accumulation and development of phenotypic drug-resistance in Mtb was established. Storage lipid biosynthetic genes may be appropriate targets for novel drugs that can kill latent Mtb.
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