Is RORγ a therapeutic target for treating Mycobacterium tuberculosis infections? - 02/02/12

Doi : 10.1016/j.tube.2011.11.009

Paul W. Baures ^⁎
Department of Chemistry, 229 Main Street, Keene State College, Keene, NH 03435-2001, USA

Tel.: +1 603 358 2769.

Summary

A link is hypothesized between inhibition of the retinoic acid receptor-related orphan receptor γ (RORγ) and treatment of Mycobacterium tuberculosis (Mtb) infection. An unexpected overlap was found between inhibitors of both Mtb H37Rv with RORγ in PubChem. Since RORγ is not present in Mtb, a commonality was reasoned to be cholesterol. Gemfibrozil is a RORγ inhibitor that was inactive against Mtb cells. Yet, gemfibrozil has been shown to inhibit Mtb growth in macrophages, supporting the hypothesis that RORγ inhibitors could show therapeutic benefit in Mtb infection.^{7Reich-Slotky R., Kabbash C.A., Della-Latta P., Blanchard J.S., Feinmark S.J., Freeman S., Kaplan G., Shuman H.A., Silverstein S.C. Gemfibrozil inhibits Legionella pneumophila and Mycobacterium tuberculosis enoyl coenzyme A reductases and blocks intracellular growth of these bacteria in macrophages J Bacteriol 2009 ; 191 : 5262-5271 [cross-ref]

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Keywords : Retinoic acid receptor-related orphan receptor γ, Mycobacterium tuberculosis, Cholesterol catabolism, Immune system function, Gemfibrozil

Plan

Introduction and hypothesis

Initial observations linking RORγ inhibitors with Mtb inhibition

What commonality is shared between some RORγ inhibitors and Mtb inhibitors?

Known functional roles of RORγ

Hydroycholesterols are native RORγ ligands

Cholesterol’s role in Mtb infectivity and persistence

Cholesterol connects inhibitors of RORγ with (some) inhibitors of Mtb

So how would a RORγ inhibitor work in a Mtb inhibition assay when the target protein is not present?

What would be the consequences of RORγ inhibition when treating Mtb infections?

Mechanism 1

Mechanism 2

What other evidence supports this hypothesis?

Testing and validating the hypothesis

Conclusion

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Vol 92 - N° 1

P. 95-99 - janvier 2012 Retour au numéro

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Is RORγ a therapeutic target for treating Mycobacterium tuberculosis infections? - 02/02/12

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