Pathogen roid rage: Cholesterol utilization by<i>Mycobacterium tuberculosis</i>

Wipperman, Matthew F.; Sampson, Nicole S.; Thomas, Suzanne T.

doi:10.3109/10409238.2014.895700

Cited by 142 publications

(165 citation statements)

References 157 publications

(267 reference statements)

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“…The metabolic network of sMtb contains 1192 reactions, 915 genes, and 929 metabolites. It includes a number of important extensions to previous models, such as the mycolic acid synthesis [29], dimycocerosate ester biosynthesis [45] and cholesterol degradation [8] pathways that have been updated according to the latest insights. In sMtb 84% of the reactions are associated with the corresponding genes, whereas in GSMN-TB 1.1 and iNJ661 these percentages are only 75% and 77%, respectively.…”

Section: A Consensus Metabolic Model Of Mtb (Smtb)mentioning

confidence: 99%

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Systems-level modeling of mycobacterial metabolism for the identification of new (multi-)drug targets

Rienksma

Suárez-Diez

Spina

et al. 2014

Seminars in Immunology

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Systems-level metabolic network reconstructions and the derived constraint-based (CB) mathematical models are efficient tools to explore bacterial metabolism. Approximately one-fourth of the Mycobacterium tuberculosis (Mtb) genome contains genes that encode proteins directly involved in its metabolism. These represent potential drug targets that can be systematically probed with CB models through the prediction of genes essential (or the combination thereof) for the pathogen to grow. However, gene essentiality depends on the growth conditions and, so far, no in vitro model precisely mimics the host at the different stages of mycobacterial infection, limiting model predictions. These limitations can be circumvented by combining expression data from in vivo samples with a validated CB model, creating an accurate description of pathogen metabolism in the host. To this end, we present here a thoroughly curated and extended genome-scale CB metabolic model of Mtb quantitatively validated using 13C measurements. We describe some of the efforts made in integrating CB models and high-throughput data to generate condition specific models, and we will discuss challenges ahead. This knowledge and the framework herein presented will enable to identify potential new drug targets, and will foster the development of optimal therapeutic strategies.

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Section: A Consensus Metabolic Model Of Mtb (Smtb)mentioning

confidence: 99%

“…Drug targets in the form of enzymes encoded by their specific genes, have been identified by gene essentiality predictions based on modeling the in vivo environment [7]. Recent insights have clarified the picture of available metabolites to Mtb inside the host and shed new light on in vivo gene essentiality predictions [8][9][10][11].…”

mentioning

confidence: 99%

Systems-level modeling of mycobacterial metabolism for the identification of new (multi-)drug targets

Rienksma

Suárez-Diez

Spina

et al. 2014

Seminars in Immunology

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“…This would lead to a branched alkyl chain, where a side chain had to be cleaved off either before or after the second ring-opening reaction. Strategies for the removal of side chains are for example known for degradation pathways of acyclic terpenoids [Forster-Fromme and Jendrossek, 2010] or steroid compounds [Philipp, 2011;Wipperman et al, 2014]. The thn operon includes two genes coding for a potential lyase ThnQS with similarities (34% identity, 51% similarities) to the putative 3-hydroxy-3-isohexenyl-glutaryl-CoA: acetate lyase AtuA from the citronellol-degrading Pseudomonas citronellolis Jendrossek, 2006, 2010].…”

Section: Towards Second Ring Cleavage: Coping With Branched Metabolitesmentioning

confidence: 99%

Anaerobic Degradation of Benzene and Polycyclic Aromatic Hydrocarbons

Meckenstock

Boll

Mouttaki³

et al. 2016

Microb Physiol

242

165

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Aromatic hydrocarbons such as benzene and polycyclic aromatic hydrocarbons (PAHs) are very slowly degraded without molecular oxygen. Here, we review the recent advances in the elucidation of the first known degradation pathways of these environmental hazards. Anaerobic degradation of benzene and PAHs has been successfully documented in the environment by metabolite analysis, compound-specific isotope analysis and microcosm studies. Subsequently, also enrichments and pure cultures were obtained that anaerobically degrade benzene, naphthalene or methylnaphthalene, and even phenanthrene, the largest PAH currently known to be degradable under anoxic conditions. Although such cultures grow very slowly, with doubling times of around 2 weeks, and produce only very little biomass in batch cultures, successful proteogenomic, transcriptomic and biochemical studies revealed novel degradation pathways with exciting biochemical reactions such as for example the carboxylation of naphthalene or the ATP-independent reduction of naphthoyl-coenzyme A. The elucidation of the first anaerobic degradation pathways of naphthalene and methylnaphthalene at the genetic and biochemical level now opens the door to studying the anaerobic metabolism and ecology of anaerobic PAH degraders. This will contribute to assessing the fate of one of the most important contaminant classes in anoxic sediments and aquifers.

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“…However, the genes within the regulon are not required for catabolism of cholesterol (8,9) suggesting an alternate role for cholesterol in Mtb survival. Recent reports suggest that cholesterol might trigger stress protection in Mtb (31, 32).…”

Section: Discussionmentioning

confidence: 99%

“…Mtb catabolism of cholesterol provides a source of acetyl-CoA, pyruvate, and propionyl-CoA, which can be utilized for energy production and supply lipid precursors to the bacterium (8). Catabolism proceeds through b-oxidation of the side chain, and oxidative cleavage of the sterol rings (9). Comparison of transcriptional profiles of Mtb cultured with or without cholesterol identified over 200 genes that are regulated by cholesterol (2).…”

Section: Introductionmentioning

confidence: 99%

The Mce3R Regulon Is Required for 6-Azasteroid Potentiation of Anti-TB Drug Activity

Yang¹,

Yuan²,

Ma³

et al. 2018

Preprint

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Mycobacterium tuberculosis (Mtb) infects humans and can live dormant within macrophages for decades, residing in a granuloma structure that arises from the host immune response and cholesterol is important for Mtb persistence in the host. Disruption of cholesterol-regulated genes results in reduced intracellular Mtb survival in animal models of infection. We phenotypically screened approximately 50 6-azasteroids against Mtb. We selected this steroid scaffold for its advantageous biophysical and pharmacokinetic properties. We found that at low micromolar concentrations a subset of 6-azasteroids sensitizes Mtb to the TB drug isoniazid and reduces the isoniazid MIC 15-30-fold. Two analogs selected for further study analogously sensitize Mtb to bedaquiline, and they improve the bactericidal activity of bedaquiline and isoniazid. Both 6-azasteroids improve the efficacy of isoniazid and bedaquiline under conditions of low oxygen, and demonstrate high synergy with bedaquiline (FIC index = 0.21, MIC BDQ = 16 nM at 1 µM 6-azasteroid). The rate of spontaneous resistance to 6-azasteroid is approximately 10 -7 and the 6-azasteroid resistance mutants retain their sensitivity to isoniazid and bedaquiline. Intriguingly, genes in the cholesterol-regulated Mce3R regulon are required for 6-azasteroid activity and genes in the cholesterol catabolism pathway are not. The Mce3R regulon has been implicated in stress resistance, and is not present in saprophytic strains of mycobacteria. We conclude that the Mce3R regulon encodes a cholesterol-dependent pathway important for pathogenesis that contributes to drug tolerance. Small molecule strategies to target the Mce3R regulon present an attractive avenue for further development of co-drugs that can improve existing tuberculosis chemotherapies. SIGNIFICANCEOne third of the world's population carries the infectious agent Mycobacterium tuberculosis (Mtb) that causes tuberculosis (TB), and every 17 seconds someone dies of TB worldwide. TB is the number one cause of death from a bacterial infectious disease. Current treatments require drug regimens of long duration to effectively cure TB disease and have many associated toxicities that are compounded by the high doses of long duration required. We have identified small molecules that increase Mtb susceptibility to existing TB drugs. The target of these small molecules is a pathway important for resistance of Mtb to stress. Development of a co-drug therapy has the potential to shorten treatment times and reduce toxicities associated with treatment of TB.

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Pathogen roid rage: Cholesterol utilization byMycobacterium tuberculosis

Cited by 142 publications

References 157 publications

Systems-level modeling of mycobacterial metabolism for the identification of new (multi-)drug targets

Systems-level modeling of mycobacterial metabolism for the identification of new (multi-)drug targets

Anaerobic Degradation of Benzene and Polycyclic Aromatic Hydrocarbons

The Mce3R Regulon Is Required for 6-Azasteroid Potentiation of Anti-TB Drug Activity

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