4.2.3. PBTZ169

*Discovery.* SAR on BTZ043 to improve its pharmacologic properties yielded PBTZ169 (now called macozinone), a piperazine derivative. Compared to BTZ043, PBTZ169 has the advantage of having no chiral center which facilitates its chemical synthesis.

*Activity.* PBTZ169 is a very potent bactericidal benzothiazinone with an MIC of 0.6 nM against *M. tuberculosis*. PBTZ169 has better potency, pharmacodynamics and is 10 times less cytotoxic than BTZ043. PBTZ169 has poor solubility in water (0.9 g/L). PBTZ169 is synergistic with BDQ and clofazimine (CFZ) but not with other new TB drugs such as delamanid, linezolid, meropenem or sutezolid [229]. Interestingly, this synergistic phenotype was also observed in non-replicating conditions where PBTZ169 has no activity [230]. In a mouse model of chronic *M. tuberculosis* infection, the reduction in lung and spleen burden was similar between INH and PBTZ169 after 4 weeks of treatment [231]. Furthermore, in a mouse model of chronic *M. tuberculosis* infection, the lung burden was reduced by 2, 4 and 4.6 log10 after 28 days of treatment with PBTZ169, CFZ and the combination PBTZ169/CFZ, respectively [230]. In a similar experiment, the combination PBTZ169/BDQ/PZA was also shown to be more efficient in reducing lung and spleen burden of chronically *M. tuberculosis*-infected mice than the standard INH/RIF/PZA treatment [231].

*Mode of action.* PBTZ169 mode of action is similar to BTZ043. PBTZ169 is a prodrug, activated by DprE1 to yield a nitroso metabolite that covalently binds to the Cys387 residue of DprE1.

*Clinical trial.* A phase I study (NCT03423030) in healthy male subjects receiving increasing doses of PBTZ169 showed that PBTZ169 was well tolerated and safe. No result has been posted for a phase 2a EBA study (NCT03334734) where PBTZ169 was given as a single dose to TB patients.

## 4.2.4. OPC167832

*Activity.* OPC167832 was developed by Otsuka pharmaceuticals. OPC167832 is a lipophilic, bactericidal compound, active against drug-susceptible, MDR and XDR *M. tuberculosis* strains, with a MIC ranging from 0.5 to 5 nM. OPC167832 is active in macrophage and in mouse model of *M. tuberculosis* infection at a dose of 1.25 mg/kg. OPC167832 is not antagonistic with other TB drugs. The combination of OPC167832 with delamanid and other TB drugs showed better efficacy than standard TB treatment in a mouse model of chronic drug-susceptible and MDR *M. tuberculosis* infections [232].

*Mode of action.* OPC167832 is a DprE1 inhibitor. OPC167832 does not contain a nitro group, and so it inhibits DprE1 via other interactions than a covalent bond with DprE1 Cys387 (see below).

*Resistance.* Spontaneous OPC167832-resistant mutants isolated at 16 × MIC occurred at a frequency of 2.6 <sup>×</sup> 10−<sup>9</sup> to 1.5 <sup>×</sup> 10−<sup>7</sup> in *M. tuberculosis* H37Rv. Mutations in *dprE1* and *Rv0678* encoding a transcriptional regulator of the efflux pumps MmpS5 and Mmpl5 [233] drive resistance to OPC167832.

*Clinical trial.* A phase 1/2 clinical trial (NCT03678688) is recruiting to test the safety, tolerability and pharmacokinetics of OPC167832 given at increasing concentrations to patients infected with uncomplicated, smear-positive, drug-susceptible TB (phase I). A phase II study will compare delamanid and OPC167832 vs. delamanid only or INH/RIF/EMB/PZA to demonstrate that this new regimen, which uses only oral drugs, is safer and can shorten TB treatment [232].
