Evaluation of the therapeutic combination and cytotoxicity of compounds 5d, Tanshinone IIA and Cryptotanshinone with therapeutic drugs against Mycobacterium Tuberculosis and resistant clinical isolates.

Abstract

Tuberculosis is one of the biggest causes of death from infection in the world, and is caused by the bacillus Mycobacterium tuberculosis (Mtb). The search for new drugs is highly prioritized, especially considering the high rate of antimicrobial resistance reported in recent years and the negative influence it has on treatmenteffectiveness. Many strategies are explored to obtain a new therapy or to recover theactivity of drugs that are already used, one of them being the investigation of possiblesynergistic effects in the association of two compounds aiming to reduce treatment time and/or greater effectiveness in Mtb elimination. The compound 1-[1-(4-chlorophenyl)-2,5-dimethyl-pyrrol-3-yl]-N-(cyclohexylmethyl) methanamine is asynthetic compound derived from N-phenyl-2,5-dimethylpyrrole, and in previous studies by our research group have already demonstrated bacteriostatic and intracellular activity against Mtb at concentrations similar to isoniazid andmoxifloxacin. It also showed low toxicity both in vitro and in vivo in a larval model of Galleria mellonella. Furthermore, the search for biological activity of substances from traditional Chinese medicine has increased, which is why we selected two tanshinones isolated from Danshen (Salvia miltiorrhiza) with studies alreadyunderway in our laboratory, to explore the synergistic capacity of these naturalcompounds, they are they: Tanshinone IIA and Cryptotanshinone. The compounds presented are considered promising candidates in the development of a new therapy for tuberculosis, which is why this project aims to evaluate the synergistic effect of compounds 5d, Tanshinone IIA and Cryptotanshinone, associated with isoniazid(INH), rifampicin (RFP), moxifloxacin (MOX) and bedaquiline (BDQ), against Mtb in vitro using the checkerboard methodology.