4.1.3. Delamanid (OPC-67683)

*Discovery.* Upon the discovery of the activity of CGI 17341 against *M. tuberculosis*, researchers at Otsuka Pharmaceutical Co., Japan, performed a SAR study on the compound to reduce its mutagenicity and increase its potency against *M. tuberculosis* [204]. The result was the nitroimidazole OPC-67683, now called delamanid.

*Activity*. Delamanid is an oral, non-mutagenic compound, poorly soluble in water (0.002 g/L). Delamanid is active in vitro (MIC 8–45 nM [205]) against drug-susceptible and MDR *M. tuberculosis* strains and highly efficacious in vivo [206]. Delamanid is also active against non-replicating *M. tuberculosis* [207]. Delamanid is only active against members of the MTB complex as well as some non-tuberculous mycobacteria and shows no activity against bacterial microflora [205]. In a mouse model of acute and chronic *M. tuberculosis* infections, delamanid performed better than PMD. After 3 weeks of treatment, in the acute model of infection, delamanid and PMD reduced the lung bacterial burden by 1 log10 and 0, respectively. In the chronic model of infection, delamanid and PMD reduced the lung bacterial burden by 3 and 2 log10, respectively [207]. Delamanid is included in the Group D2 (add-on agents) of second-line TB drugs to treat RIF-resistant and MDR TB patients.

*Mode of action.* Similar to PMD, delamanid is a prodrug activated by the deazaflavin-dependent nitroreductase Ddn to form a des nitro metabolite and release NO. Delamanid inhibits the biosynthesis of methoxy- and keto-mycolic acids but not of α-mycolic acids [206]. Deciphering the mechanism of action of delamanid by isolating spontaneous in vitro resistant mutants has led to the identification of mutations in genes involved only in delamanid activation (*ddn, fgd1, fbiABC*), not in its target [208]. Frequency of mutation was relatively high (10−<sup>5</sup> to 10<sup>−</sup>6). Complementation restored drug susceptibility except for one *fbiB* mutant that required complementation with a plasmid containing both *fbiB* and *fbiA*. Two delamanid-resistant clinical isolates were also analyzed in that study and shown to have mutations in *ddn* (L107P and a 59–101 bp deletion). The target of delamanid is yet to be discovered, as no mutant in pathways independent to delamanid's mode of activation has been isolated. The question remains as to whether delamanid and PMD target mycolic acid biosynthesis or whether the inhibition of the biosynthesis of these specific mycolic acids observed during delamanid or PMD treatment of *M. tuberculosis* is only a consequence of the inhibition of these compounds' target(s).

*Clinical trial.* As of 2019, delamanid is one of three new TB drugs in phase 3 clinical development along with PMD and BDQ (www.newtbdrugs.org). In a clinical trial in MDR TB patients, delamanid was added for 2 months to an optimized background treatment regimen (OBR), resulting in 45% sputum culture conversion compared to 30% sputum culture conversion for the patients getting OBR and placebo [209]. In this study, the group of patients receiving higher doses of delamanid (200 mg, twice a day) had a higher incidence of palpitation and prolonged QT intervals than the groups that received a lower concentration (100 mg, twice a day) of delamanid or placebo. In a subsequent six-month delamanid trial, a lower mortality rate was observed in TB patients that received delamanid for 6 months rather than the previous 2 months trial, but no significant difference in successful treatment outcome was recorded between the 2 month and 6 month delamanid trial [210,211]. A phase 3 clinical trial on MDR TB patients tested the addition of delamanid for the first six months of the 24 month OBR regimen. There was no statistical difference in time to sputum culture conversion or rate of adverse events whether the patients received delamanid or not with their OBR treatment [212]. Overall, delamanid is a well-tolerated drug with good safety data. In 2014, delamanid was approved for the treatment of pulmonary MDR TB in adults in Europe, Japan and Korea.

Delamanid, PMD and SQ109 are the only drugs in advanced clinical development so far targeting mycolic acid biosynthesis or mycolic acid incorporation into the cell wall. Academic and pharmaceutical laboratories are developing new inhibitors of enzymes involved in mycolic acid biosynthesis. Inhibitors of KasA [213], InhA [83,90–92], Pks13 [214–217] and Mmpl3 [185,190,191,218,219] are being tested.
