Effect of urolithin A on intracellular survival of Mycobacterium tuberculosis by regulating AKT-FOXO1-mediated autophagy.

Tuberculosis (TB), resulting from Mycobacterium tuberculosis (Mtb), is one of the leading causes of morbidity and mortality in humans worldwide. Host-directed therapy (HDT) is a novel approach for treating TB, particularly those with drug resistance. Urolithin A (UroA) produced through bioconversion of plant-derived ellagic acid by gut microbes has been proven to have multiple beneficial effects in a variety of diseases without showing undesired adverse reactions. However, whether UroA has antimycobacterial effect and the underlying mechanism has not yet been reported. Here, we found that UroA significantly inhibited Mtb growth within both macrophages and mice. Moreover, UroA promoted the activation of autophagy in Mtb-infected macrophages via the protein kinase B-Forkhead box protein O1 signaling pathway, which contributed to the antimycobacterial effect of UroA. Additionally, UroA suppressed the survival of clinically isoniazid (INH)-resistant Mtb (C2) within macrophages, and the combination of UroA and INH synergistically enhanced host elimination of Mtb H37Rv. Therefore, UroA may be utilized as a potential candidate for HDT and as an adjunctive therapy with first-line anti-TB drugs.IMPORTANCEHost-directed therapy (HDT) is a novel approach for treating tuberculosis (TB), particularly those with drug resistance. Urolithin A (UroA) produced through bioconversion of plant-derived ellagic acid by gut microbes has been proven to have multiple beneficial effects in a variety of diseases without showing undesired adverse reactions. We found that UroA significantly inhibited Mycobacterium tuberculosis (Mtb) growth within macrophages. Moreover, UroA suppressed the survival of clinically isoniazid (INH)-resistant Mtb (C2) within macrophages, and the combination of UroA and INH synergistically enhanced host elimination of Mtb H37Rv. Therefore, UroA may be utilized as a potential candidate for HDT and as an adjunctive therapy with first-line anti-TB drugs.