4.2.1. CPZEN-45

*Discovery.* Caprazamycin B, a liponucleoside isolated from *Streptomyces,* is a non-toxic antibiotic with good activity in vitro (MIC 3–11 μm) against drug-susceptible and MDR *M. tuberculosis* strains but insoluble in water [220]. To increase its hydrophilicity, SAR was performed and led to the nucleoside caprazene-45 (CPZEN-45) [221].

*Activity*. CPZEN-45 is a water-soluble drug (solubility ≈ 10 g/L) with an MIC of 2–5 μm and 10 μm against drug-susceptible and MDR *M. tuberculosis,* respectively. Unlike caprazamycin B, which is active against several Gram-positive bacteria, CPZEN-45 has no activity against *S. aureus, Streptococcus pneumonia* or *Enterococcus faecalis* [222]. CPZEN-45 is specific to slow-growing pathogens. In mice intravenously infected with the drug-susceptible *M. tuberculosis* H37Rv strain, a 30-day subcutaneous treatment with CPZEN-45 was as effective in reducing lung burden as INH and better than RIF alone [223]. Furthermore, the combination INH/RIF/CPZEN-45 resulted in at least a 1 log10 better killing of *M. tuberculosis* than the combination INH/RIF. In a subsequent experiment, mice were intravenously infected with an XDR *M. tuberculosis* strain and treated with CPZEN-45 at doses ranging from 6.3 to 200 mg/kg. After 30 days, the mice treated with the highest concentration of CPZEN-45 had a 1.5 log10 better reduction in CFUs in the lungs than the mice receiving the lowest concentration [223].

*Mode of action.* CPZEN-45 is an inhibitor of *M. tuberculosis* WecA (Rv1302) with an IC50 of 7 nM [222]. WecA is involved in the first step of the arabinogalactan biosynthesis forming the anchor point between peptidoglycan and arabinogalactan. Transcriptionally silencing *wecA* is bactericidal in *M. tuberculosis* in vitro and bacteriostatic ex vivo, validating WecA as candidate for drug development [224].

*Clinical trial.* CPZEN-45 is in the early stage of clinical development.
