Cholesterol catabolism as a therapeutic target in Mycobacterium tuberculosis

Abstract

Mycobacterium tuberculosis (Mtb) is an intracellular pathogen that infects 10 million worldwide and kills 2 million people every year. The uptake and utilization of nutrients by Mtb within the host cell is still poorly understood, although lipids play an important role in Mtb persistence. The recent identification of a large regulon of cholesterol catabolic genes suggests that Mtb can use host sterol for infection and persistence. In this review, we report on recent progress in elucidation of the Mtb cholesterol catabolic reactions and their potential utility as targets for tuberculosis therapeutic agents.

Preliminary Evaluation of Artemisinin–Cholesterol Conjugates as Potential Drugs for the Treatment of Intractable Forms of Malaria and Tuberculosis

“…[27,28] In the human liver,t he malaria parasite associates with the endoplasmic reticulum (ER)i nh epatocytes so that it may salvagen ewly synthesized lipids. The parasite also continuously diverts cholesterol from low-density lipoproteins and hepatocytes duringt he liver stage.…”

Substrate Uptake and Subcellular Compartmentation of Anoxic Cholesterol Catabolism in Sterolibacterium denitrificans

“…26-Hydroxycholest-4-en-3-one (also named 27-hydroxy-4-cholesten-3-one, 99%) and cholest-4-en-3-one-26-oic acid (also named 3-oxo-4-cholestenoic acid, 99%) were obtained from Avanti Polar Lipids, and cholest-4-en-3-one-24-oic acid (also named 4-cholenic acid-3-one) and pregn-4-en-3-one-20-carboxylic acid (also named 4-pregnen-3-one-20␤-carboxylic acid) were purchased from Steraloids. Cholesterol, [4C- 13 C]cholesterol (99 atom % 13 C), cholest-4-en-3-one, cholesta-1,4-diene-3-one, androst-4-en-3,17-dione (AD), and androsta-1,4-diene-3,17-dione (ADD) were obtained from Sigma. S. denitrificans Chol-1S T (DSMZ 13999) was purchased from the Deutsche Sammlung für Mikroorganismen und Zellkulturen (Braunschweig, Germany).…”

“…After the consumption of cholesterol, 20 ml of the log phase culture was transferred to a sterile 25-ml glass bottle sealed with a rubber stopper. The S. denitrificans cells were subsequently fed with 1 mM [4C- 13 C]cholesterol and anaerobically incubated at 28°C with stirring (120 rpm). Samples (0.5 ml) were withdrawn every 2 h (0 -24 h).…”

“…Here, we investigated microbial cholesterol catabolism at the subcellular level. 13 C metabolomic analysis revealed that anaerobically grown Sterolibacterium denitrificans, a ␤-proteobacterium, adopts an oxygenase-independent pathway to degrade cholesterol. S. denitrificans cells did not produce biosurfactants upon growth on cholesterol and exhibited high cell surface hydrophobicity.…”

“…Identification of a large regulon of cholesterol catabolic genes suggested that the utilization of host sterols is crucial for infection and persistence of Mycobacterium tuberculosis in macrophages (12). Recent progress in the investigation of the cholesterol catabolic reactions of M. tuberculosis indicated that cholesterol catabolism can be used as a therapeutic target in this human pathogen (13). Researchers have explored the cholesterol uptake of M. tuberculosis within the host cell extensively and identified an ATP-binding cassette-like cholesterol transport system, mce4, in M. tuberculosis (11,14,15).…”