**7. Conclusions**

The ultimate goal of the TB drug-development efforts is a design of new, more effective regimen, which could replace the current combination therapy. One of the most promising DprE1 inhibitors is macozinone. Its safety and tolerability profiles, pharmacokinetics, and efficacy in terms of early bactericidal activity were evaluated in the course of three clinical trials conducted by Nearmedic Plus LLC in the Russian Federation, two clinical trials by iM4TB foundation are in progress. High tolerability and a favorable safety profile of the drug in the studied dose range were demonstrated both in healthy volunteers and in patients with newly diagnosed pulmonary tuberculosis with bacterial excretion and preserved sensitivity to isoniazid and rifampicin. The main pharmacokinetics parameters of macozinone after single and multiple administration in the dosage range up to 1280 mg were studied, and a statistically significant efficacy of the drug after monotherapy at a dose of 640 mg a day was established, which allowed the preferred regimen of its intake to be determined.

A thorough study aimed at interactions of macozinone with a spectrum of clinically used and experimental TB drugs was recently performed [30]. It revealed that macozinone does not have synergistic or antagonistic interactions with the tested first-line (rifampin, isoniazid, ethambutol) or second-line (amikacin, levofloxacin, moxifloxacin, D-cycloserin, ethionamide, *para*-aminosalicyc acid) drugs. Among the tested re-purposed or new drugs, clarithromycin, delamanid, lansoprazole sulfide, linezolid, meropenem or sutezolid did not show synergistic effects, when tested individually with macozinone by the checkerboard assay. Synergism was observed for macozinone and clofazimine or bedaquiline, confirming previous findings [20,41]. At the same time, enumeration of colony forming units after drug exposure revealed the next two potentially synergistic candidates—delamanid and sutezolid. In the mouse model of TB, the combination of macozinone-delamanid-sutezolid was more active in the lungs of *M. tuberculosis*-infected animals compared to the regimen of rifampin-isoniazid-pyrazinamide, while the bacterial burden in spleen remained comparable. However, increased toxicity of the combination for HepG2 cells was observed, so further studies are needed to evaluate the potential of this drug combination [30]. Nevertheless, neither antagonism nor increased toxicity was found for most combinations, which paves the way for using macozinone in the development of more efficient TB regimens [30].

**Author Contributions:** Both authors contributed to writing of the paper. All authors have read and agreed to the published version of the manuscript.

**Funding:** K.M. acknowledges current support by Slovak Research and Development Agency (APVV-15-0515).

**Acknowledgments:** Authors would like to thank Nearmedic Plus LLC, and personally to R. Bolgarin for information concerning clinical trials and preclinical studies including unpublished data.

**Conflicts of Interest:** V.M. is a named inventor on patents pertaining to work on benzothiazinones mentioned herein. K.M. declares no conflict of interest.
