Benzothiazinethione is a potent preclinical candidate for the treatment of drug-resistant tuberculosis

Abstract

New chemotherapeutic compounds are needed to combat multidrug-resistant Mycobacterium tuberculosis (Mtb), which remains a serious public-health challenge. Decaprenylphosphoryl-β-D-ribose 2′-epimerase (DprE1 enzyme) has been characterized as an attractive therapeutic target to address this urgent demand. Herein, we have identified a new class of DprE1 inhibitors benzothiazinethiones as antitubercular agents. Benzothiazinethione analogue SKLB-TB1001 exhibited excellent activity against Mtb in the Microplate Alamar blue assay and intracellular model, meanwhile SKLB-TB1001 was also highly potent against multi-drug resistant extensively and drug resistant clinical isolates. Importantly, no antagonism interaction was found with any two-drug combinations tested in the present study and the combination of SKLB-TB1001 with rifampicin (RMP) was proved to be synergistic. Furthermore, benzothiazinethione showed superb in vivo antitubercular efficacy in an acute Mtb infection mouse model, significantly better than that of BTZ043. These data combined with the bioavailability and safety profiles of benzothiazinethione indicates SKLB-TB1001 is a promising preclinical candidate for the treatment of drug-resistant tuberculosis.

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

“…Gao et al. identified an S ‐acetal BTZ analogue ( 251 ) as being more potent in vitro than BTZ‐038, while similarly a thioamide (SKLB‐TB1001, 252 ) analogue was identified having superior in vivo activity in acute murine models of infection than 248 coupled to good bioavailability and safety profiles . In an effort to improve the pharmacokinetic properties of BTZ compounds, Karoli et al .…”

Metabolism of SKLB-TB1001, a Potent Antituberculosis Agent, in Animals

“…area under the concentration-time curve (AUC) with the intravenous (i.v.) AUC of SKLB-TB1001 in plasma over time showed an apparent oral bioavailability of 44.4% (50-mg/kg dose), which was significantly higher than that of BTZ043 (F ϭ 29.5%) (10). These results indicated that SKLB-TB1001 had adequate PK properties for in vivo efficacy.…”

“…We recently reported a new benzothiazinethione, SKLB-TB1001, which had promising antitubercular potency against drug-sensitive, as well as MDR and XDR, M. tuberculosis in vitro at nanomolar concentrations. In addition, additive to synergistic interactions were observed when SKLB-TB1001 was combined with other TB drugs in checkerboard assays (10,11). However, although SKLB-TB1001 showed excellent antitubercular efficacy in vitro, it was less effective in a murine model in further studies.…”

“…Considering that absorption, distribution, metabolism, and excretion (ADME) always dramatically influence drug potency in vivo, the pharmacokinetics (PK) of orally administered SKLB-TB1001 and BTZ043 were analyzed. The moderate elimination half-life (t 1/2 ϭ 1.45 h for SKLB-TB1001 and 1.22 h for BTZ043) indicated the high correlation between the attenuated potency in vivo and their poor ADME profiles (10). Here, we investigated the biotransformation and metabolic pathways of SKLB-TB1001 in animals.…”

Redox‐guided small molecule antimycobacterials

“…Tiwari et al and Gao et al have worked on modifying the BTZ scaffold and have proposed some potent DprE1 inhibitors through their structure–activity relationship study. Some of these compounds such as SKLB‐TB1001 are potent preclinical candidates in the treatment of drug‐resistant TB.…”