Drug repurposing: An antidiabetic drug Ipragliflozin as Mycobacterium tuberculosis sirtuin-like protein inhibitor that synergizes with anti-tuberculosis drug isoniazid

The surge of drug-resistant Mycobacterium tuberculosis (DR-TB) impedes the World Health Organization's efforts in ending TB and calls for new therapeutic formulations. M. tuberculosis sirtuin-like protein Rv1151c is a bifunctional enzyme with both deacetylation and desuccinylation activities, which plays an important role in M. tuberculosis drug resistance and stress responses. Thus, it appears to be a promising target for the development of new TB therapeutics. In this study, we screened 31,057 ligand compounds from seven compound libraries in silico to identify inhibitors of Rv1151c. Ipragliflozin can bind to Rv1151c and interact stably. Ipragliflozin can change the acylation level of M. tuberculosis by inhibiting Rv1151c and effectively inhibit the growth of M. tuberculosis H37Rv and M. smegmatis. It can potentiate the first-front anti-TB drug isoniazid. As an antidiabetic drug, Ipragliflozin can be potentially included in the regimen to treat diabetes-tuberculosis comorbidity.