# Mycobacterial Cell Wall: A Source of Successful Targets for Old and New Drugs
## 4 New Generation of Cell Wall Inhibitors
### Target: Mycolic Acids
#### 4.1.2 Pretomanid (PA-824)
tuberculosis_ treated with PMD under replicating conditions revealed that PMD action had similarity with cell wall inhibitors as well as inhibitors of the respiratory chain [199]. This data confirmed the dual action of PMD as an inhibitor of a subfamily of mycolic acids as well as a NO generator leading to the inhibition of the respiratory chain under anaerobic conditions. This combination of a cell wall inhibitor and NO generator makes PMD a unique antimycobacterial drug, effective against active and dormant TB that can shorten the duration of chemotherapy. _Resistance._ The main mechanism of resistance to PMD is through mutations in its activator Ddn. In vitro selection of spontaneous PMD-resistant mutants in _M. tuberculosis_ led to the isolation of 183 mutants [200]. The mutation rate was relatively high ranging from 10\({}^{-5}\) to 10\({}^{-7}\). Most of the mutations were in _ddn_ (SNPs, base pair deletion or insertion, early stop codon). Mutations in _ftiABC_ (_Rv3261_, _Rv3262_, _Rv1173_) encoding F420 biosynthesis proteins and _fgd1_ (_Rv0407_) encoding a F420-dependent glucose-6-phosphate dehydrogenase were also identified, but no complementation experiments were performed to confirm the role of these mutations in PMD resistance. _Clinical trial._ A phase 2a clinical trial (NCT01215851) evaluated the early bactericidal activity (EBA), safety and tolerability of PMD combined with BDQ, PZA and/or MXF in newly diagnosed drug-susceptible, smear-positive pulmonary TB patients [201]. These combinations were well tolerated and seemed safe. The combination PMD/PZA/MXF was more bactericidal than PMD/BDQ or PMD/PZA and as potent as the standard regimen (INH/RIF/EMB/PZA) [201]. In a phase 2b clinical trial (NCT02193776), the efficacy, safety and tolerability of the combination PMD/BDQ/PZA were assessed in newly diagnosed drug-susceptible, smear-positive pulmonary TB patients treated for 8 weeks [202]. TB patients converted more rapidly to sputum negativity with PMD/BDQ/PZA than the standard regimen. One arm of the study also looked at the combination PMD/BDQ/PZA/MXF for the treatment of newly diagnosed, MXF-sensitive, MDR, pulmonary TB patients. MDR TB patients converted to sputum negativity within 8 weeks of treatment with PMD/BDQ/PZA/MXF. A phase 2c trial (NCT03338621) is currently in progress to evaluate the efficacy, safety and tolerability of a 4 month PMD/BDQ/PZA/MXF treatment given to patients infected with drug-sensitive TB or a 6 month treatment given to drug-resistant TB patients. No results have been posted yet. The Nix-TB trial (phase 3, NCT02333799) was set to test the efficacy, tolerability, safety and pharmacodynamics of the combination PMD/BDQ/LZD given for six months on 50 patients infected with XDR TB and 24 patients infected with treatment-intolerant or non-responsive MDR TB. 88% of XDR TB cases and 92% of MDR TB cases had favorable outcomes at the end of treatment (no clinical infection, culture negative 6 months post treatment). 23% of the patients had manageable adverse effects [203]. On August 14, 2019, the Food and Drug Administration (FDA) approved the use of PMD in combination with BDQ and LZD for the treatment of pulmonary TB only in the case of non-responsive MDR, XDRand treatment-intolerant _M. tuberculosis_ infections. This new regimen is all oral, short (6 months), more efficacious (sputum conversion in less than 6 weeks) and uses fewer drugs (3) compared to the treatment for highly resistant TB, which entails daily injections for 6 months followed by daily treatment with five drugs for 12 to 18 months ([[https://www.fda.gov/media/128001/download](https://www.fda.gov/media/128001/download)]([https://www.fda.gov/media/128001/download](https://www.fda.gov/media/128001/download))).