**6. Other DprE1 Inhibitors under Active Clinical Development**

Following the discovery of DprE1 as a target of BTZ043, numerous molecules acting on this enzyme emerged, particularly from the whole-cell based phenotypic screening campaigns (for a recent review see [32]). As a result, DprE1 was given an unflattering attribute—a promiscuous target [33]. Nevertheless, DprE1 remains to be one of the best understood and the most vulnerable novel targets. One of the reasons for its high sensitivity against a number of different pharmacophores could be its periplasmic localization, which makes it easily accessible for the drugs [34]. Consequently, in addition to macozinone, there are currently three other DprE1 inhibitors progressing down the clinical studies pipeline. BTZ043, sponsored by the University of Munich; the Hans Knöll Institute, Jena; and the German Center for Infection Research, successfully completed a single dose escalation Phase 1 study (NCT03590600) [35] and is currently recruiting for a combined Phase 1 and 2 study, which will evaluate safety, tolerability, pharmacokinetics and early bactericidal activity of the multiple ascending doses (NCT04044001) [36]. A non-covalent DprE1 inhibitor, TBA-7371 [37] developed by TB Alliance, Bill and Melinda Gates Medical Research Institute and Foundation for Neglected Disease Research, completed a Phase 1 study (NCT03199339) [38]—a partially blind, placebo-controlled study of (i) a combined single ascending dose with a food effect cohort, (ii) multiple ascending dose group, and (iii) a cohort to investigate interactions between TBA-7371 with midazolam and bupropion. Currently, recruitment of adult patients with rifampicin-sensitive pulmonary tuberculosis is taking place for the participation in a Phase 2 study (NCT04176250) [39] to assess safety, early bactericidal activity, and pharmacokinetics of escalating doses of TBA-7371. A combined Phase 1 and 2 study of OPC-167832 by Otsuka is in progress (NCT03678688) [40], aimed at evaluation of the safety, tolerability, pharmacokinetics, and efficacy of multiple oral doses of the drug in patients with uncomplicated drug-sensitive pulmonary tuberculosis with a positive smear. In a parallel group, low dose or high dose OPC-167832 will be combined with delamanid and compared to delamanid only, or standard treatment with isoniazid, rifampin, pyrazinamide, and ethambutol.
