Potential Effect of Statins on<i>Mycobacterium tuberculosis</i>Infection

Guerra-de-Blas, Paola del Carmen; Torres-González, Pedro; Bobadilla-del-Valle, Miriam; Sada‐Ovalle, Isabel; Ponce-De-León-Garduño, Alfredo; Sifuentes–Osornio, José

doi:10.1155/2018/7617023

Cited by 23 publications

(17 citation statements)

References 108 publications

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“…2 In clinical practice, statins (that can decrease plasma cholesterol levels and increase the resistance to M. tuberculosis infection) have been used to treat TB patients. 39 Therefore, blocking CE synthesis in M. tuberculosis may be the adjuvant therapeutic target for anti-TB medications.…”

Section: Discussionmentioning

confidence: 99%

Identification of potential lipid biomarkers for active pulmonary tuberculosis using ultra-high-performance liquid chromatography-tandem mass spectrometry

Han

Chen

et al. 2020

Exp Biol Med (Maywood)

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Early diagnosis of active pulmonary tuberculosis (TB) is the key to controlling the disease. Host lipids are nutrient sources for the metabolism of Mycobacterium tuberculosis. In this research work, we used ultra-high-performance liquid chromatography-tandem mass spectrometry to screen plasma lipids in TB patients, lung cancer patients, community-acquired pneumonia patients, and normal healthy controls. Principal component analysis, orthogonal partial least squares discriminant analysis, and K-means clustering algorithm analysis were used to identify lipids with differential abundance. A total of 22 differential lipids were filtered out among all subjects. The plasma phospholipid levels were decreased, while the cholesterol ester levels were increased in patients with TB. We speculate that the infection of M. tuberculosis may regulate the lipid metabolism of TB patients and may promote host-assisted bacterial degradation of phospholipids and accumulation of cholesterol esters. This may be related to the formation of lung cavities with caseous necrosis. The results of receiver operating characteristic curve analysis revealed four lipids such as phosphatidylcholine (PC, 12:0/22:2), PC (16:0/18:2), cholesteryl ester (20:3), and sphingomyelin (d18:0/18:1) as potential biomarkers for early diagnosis of TB. The diagnostic model was fitted by using logistic regression analysis and combining the above four lipids with a sensitivity of 92.9%, a specificity of 82.4%, and the area under the curve (AUC) value of 0.934 (95% CI 0.873 – 0.971). The machine learning method (10-fold cross-validation) demonstrated that the model had good accuracy (0.908 AUC, 85.3% sensitivity, and 85.9% specificity). The lipids identified in this study may serve as novel biomarkers in TB diagnosis. Our research may pave the foundation for understanding the pathogenesis of TB.

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Section: Discussionmentioning

confidence: 99%

Identification of potential lipid biomarkers for active pulmonary tuberculosis using ultra-high-performance liquid chromatography-tandem mass spectrometry

Han

Chen

et al. 2020

Exp Biol Med (Maywood)

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“…Although metformin treatment of patients suffering from diabetes mellitus (DM) lowered the prevalence of latent tuberculosis infection (LTBI) 33 , it failed to show an anti-TB effect in DM patients with pulmonary active TB 34 , 35 . Statins have similarly been shown to lower LTBI prevalence 33 , but in addition have pleiotropic effects on the host response, which can both positively and negatively impact treatment outcome 36 . Nitazoxanide has been shown to have host-directed activity against Mtb by inducing autophagy, although it also has direct antimicrobial activity 37 .…”

Section: Introductionmentioning

confidence: 99%

Repurposing diphenylbutylpiperidine-class antipsychotic drugs for host-directed therapy of Mycobacterium tuberculosis and Salmonella enterica infections

Heemskerk

Korbee

Esselink

et al. 2021

Sci Rep

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The persistent increase of multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) infections negatively impacts Tuberculosis treatment outcomes. Host-directed therapies (HDT) pose an complementing strategy, particularly since Mtb is highly successful in evading host-defense by manipulating host-signaling pathways. Here, we screened a library containing autophagy-modulating compounds for their ability to inhibit intracellular Mtb-bacteria. Several active compounds were identified, including two drugs of the diphenylbutylpiperidine-class, Fluspirilene and Pimozide, commonly used as antipsychotics. Both molecules inhibited intracellular Mtb in pro- as well as anti-inflammatory primary human macrophages in a host-directed manner and synergized with conventional anti-bacterials. Importantly, these inhibitory effects extended to MDR-Mtb strains and the unrelated intracellular pathogen, Salmonella enterica serovar Typhimurium (Stm). Mechanistically Fluspirilene and Pimozide were shown to regulate autophagy and alter the lysosomal response, partly correlating with increased bacterial localization to autophago(lyso)somes. Pimozide’s and Fluspirilene’s efficacy was inhibited by antioxidants, suggesting involvement of the oxidative-stress response in Mtb growth control. Furthermore, Fluspirilene and especially Pimozide counteracted Mtb-induced STAT5 phosphorylation, thereby reducing Mtb phagosome-localized CISH that promotes phagosomal acidification. In conclusion, two approved antipsychotic drugs, Pimozide and Fluspirilene, constitute highly promising and rapidly translatable candidates for HDT against Mtb and Stm and act by modulating the autophagic/lysosomal response by multiple mechanisms.

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“…The course of infection with a wide range of agents has been reported to be affected by statins. These include methicillinsensitive Staphylococcus aureus (12), Clostridium difficile (13), Mycobacterium tuberculosis (14), Chlamydophila pneumoniae (15), Plasmodium falciparum (16), Candida albicans, Aspergillusfumigatus (17), hepatitis C virus (18), Epstein-Barr virus (19) and type B Coxsackievirus (CVB) (20).…”

Section: Statins In Infectious Diseasesmentioning

confidence: 99%