# Mycobacterial Cell Wall: A Source of Successful Targets for Old and New Drugs
## 4 New Generation of Cell Wall Inhibitors
### Target: Mycolic Acids
#### 4.1.3 Delamamid (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 delamamid. _Activity._ Delamamid is an oral, non-mutagenic compound, poorly soluble in water (0.002 g/L). Delamamid is active in vitro (MIC 8-45 nM [205]) against drug-susceptible and MDR _M. tuberculosis_ strains and highly efficacious in vivo [206]. Delamamid is also active against non-replicating _M. tuberculosis_[207]. Delamamid 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, delamamid performed better than PMD. After 3 weeks of treatment, in the acute model of infection, delamamid and PMD reduced the lung bacterial burden by 1 log\({}_{10}\) and 0, respectively. In the chronic model of infection, delamamid and PMD reduced the lung bacterial burden by 3 and 2 log\({}_{10}\), respectively [207]. Delamamid 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, delamamid is a prodrug activated by the deazaflavin-dependent nitroreductase Ddn to form a des nitro metabolite and release NO. Delamamid inhibits the biosynthesis of methoxy- and keto-mycolic acids but not of \(\alpha\)-mycolic acids [206]. Deciphering the mechanism of action of delamamid by isolating spontaneous in vitro resistant mutants has led to the identification of mutations in genes involved only in delamamid activation (_ddn_, _fgd1_, _fbiABC_), not in its target [208]. Frequency of mutation was relatively high (\(10^{-5}\) to \(10^{-6}\)). Complementation restored drug susceptibility except for one _fbiB_ mutant that required complementation with a plasmid containing both _fbiB_ and _fbiA_. Two delamamid-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 delamamid is yet to be discovered, as no mutant in pathways independent to delamamid's mode of activation has been isolated. The question remains as to whether delamamid and PMD target mycolic acid biosynthesis or whether the inhibition of the biosynthesis of these specific mycolic acids observed during delamamid or PMD treatment of _M. tuberculosis_ is only a consequence of the inhibition of these compounds' target(s). _Clinical trial._ As of 2019, delamamid 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, delamamid 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 delamamid (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 delamamid or placebo. In a subsequent six-month delamamid trial, a lower mortality rate was observed in TB patients that received delamamid 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 delamamid trial [210,211]. A phase 3 clinical trial on MDR TB patients tested the addition of delamamid 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 delamamid or not with their OBR treatment [212]. Overall, delamamid is a well-tolerated drug with good safety data.