# Mycobacterial Cell Wall: A Source of Successful Targets for Old and New Drugs
## 3 Old TB Drugs  
### Isoniaid--Target: Mycolic Acids  
**Discovery. ** In 1949, [PERSON] and [PERSON] went to Germany to investigate reports that TB patients were successfully treated with a new synthetic compound, Conteben [36]. Conteben, a thiosemicarbazone also known as thiacetazone and Tibione (see thiacetazone section below), had been discovered by [PERSON] at Bayer in West Germany. [PERSON] and [PERSON] returned to the USA with a supply of Conteben. After testing of Conteben in US hospitals, they concluded that \"a prompt and thorough series of experimental and clinical trials in the United States\" was justified along with experimenting with other thiosemicarbazones [37]. Two US pharmaceutical companies, Hoffman-La Roche and E. R. Squibb & Sons, quickly developed a series of thiosemicarbazone analogs but none showed better activity than Conteben [38; 39; 40] until the benzene ring in Conteben was replaced with a pyridine ring leading to the simultaneous discovery of Rimifon at Hoffman-La Roche [39] and Nydrazid at Squibb [41]. In parallel, [PERSON] at Bayer developed the thiosemicarbazone analog Neoteben [42]. Rimifon, Nydrazid and Neoteben had antiTB activity that far exceeded streptomycin, PAS and any other analog synthesized so far and share the same chemical structure: 4-pyridinecarboxylic acid hydrazide. Hoffman-La Roche, Squibb and Bayer had simultaneously and independently discovered the most potent TB drug at the time: isoniaizid (INH). Ironically, none of the pharmaceutical companies could patent their discovery, as INH had been synthesized 40 years earlier by two Polish graduate students [PERSON] and [PERSON] [36]. The results with INH were so striking that chemotherapy became the leading route for TB treatment, and soon after the sanatoria closed. Almost 70 years later, INH remains the cornerstone of TB chemotherapy for the treatment of drug-susceptible and latent _M. tuberculosis_ infections. **Activity and toxicity. ** INH is a first-line TB drug. INH is an oral, highly soluble in water (140 g/L), bactericidal drug with a minimum inhibitory concentration (MIC) ranging from 0.1 to 0.7 \(\upmu\)m against _M. tuberculosis._ In vitro, INH rapidly reduces the number of _M. tuberculosis_ bacteria by 2- to 3-log\({}_{10}\)s during the first four days of treatment [43]. This bactericidal activity is only observed in exponentially growing _M. tuberculosis_ cultures. INH has no activity in stationary or persistent _M. tuberculosis._ In mice, a similar pattern is observed, where INH is bactericidal only on actively dividing _M. tuberculosis_[44]. INH is readily absorbed and reaches concentrations in tissues and organs above its MIC. The main adverse effect of INH is hepatotoxicity. TB patients more likely to develop liver damage when taking INH are slow acetylators [45; 46]. INH is acetylated into the inactive molecule AcINH by the human _N_-acetyltransferase-2 (NAT2), which is expressed mostly in the liver and gastrointestinal tract. Genetic polymorphisms in NAT2 renders this acetylation reaction either slow or fast, dividing TB patients between slow and fast acetylators. INH metabolism also involves an amidase metabolizing INH into an hydrazine (Hz), which is then acetylated by NAT2 to form a toxic acylhydrazine (AcHz) and a non-toxic diacylhydrazine (DiAcHz) [46]. Hz, AcHz and their metabolites generated by the -lived microsomal cytochrome P450 enzymes have been linked to liver toxicity [47; 48]. Fast acetylators have a lower risk of liver toxicity by producing more of the DiAcHz metabolite and less of the AcHz metabolite(s) [49]. _Mode of action._ INH enters _M. tuberculosis_ cells by passive diffusion as a prodrug. A prodrug is the ideal drug where the compound has, if possible, no effect on eukaryotic cells, yet, once activated by a pathogen-specific enzyme, leads to the death of the pathogen [50]. Curiously, the TB pharmacopeia is composed of an array of prodrugs approved for clinical therapy as well as in the developmental phase [51].