# Mycobacterial Cell Wall: A Source of Successful Targets for Old and New Drugs
## 3 Old TB Drugs
### Cycloserine--Target: Peptidoglycan  
_Discovery._ In contrast to INH, EMB and ETH, which are synthetic compounds, cyclosporine is a natural product produced by _Streptomyces_ with broad-spectrum activity. Cycloserine (D-4-amino-3-isoxazolidone, also called oxamycin or seromycin) was isolated from _Streptomyces__graphalus_[139], _Streptomyces__lavendulae_[140], _Streptomyces__rosochromogens_[141] and _Streptomyces__proidacous_[142] in the early 1950s. _Activity and toxicity._ Cycloserine is an oral drug, highly soluble in water (877 g/L). Cycloserine is a bacteriostatic second-line TB drug, with a MIC ranging from 50 to 250 \(\upmu\)m against drug-susceptible _M. tuberculosis._ An analog of cyclosporine, terizidone, a compound made of two molecules of cyclosporine, is also used as a second-line TB drug to treat MDR TB. Cycloserine was shown to inhibit the growth of _M. tuberculosis_ in vitro [143]. In vivo, cycloserine is rather inactive in a mouse or guinea pig model of _M. tuberculosis_ infection [143; 144; 145] but effective in _M. tuberculosis_-infected monkeys and humans [146; 147; 148]. The differences in cyclosporine activity in animal models were correlated with levels of D-alanine in sera [149] and rate of cycloserine excretion [146]. In a cohort study in China, TB patients with MDR TB had a better outcome when cycloserine was added to the treatment but that was not the case for TB patients infected with pre-XDR or XDR _M. tuberculosis_ strains [150]. As an inhibitor of peptidoglycan biosynthesis, cycloserine has the distinctive feature of having a unique mechanism of action thus preventing any cross resistance with other first-line and second-line TB drugs. Cycloserine is, therefore, a useful addition to second-line TB drugs, although its use might be limited by its severe toxicity. Serious adverse effects were observed during cycloserine treatment such as neuropathy and behavioral changes [151]. Cycloserine is, therefore, contraindicated in patients suffering from severe depression, suicidal tendencies, kidney failure, epilepsy or seizures. _Mode of action._ The mechanism of action of cycloserine was primarily deciphered in _Staphylococcus aureus._ Cycloserine is an analog of D-alanine and works as an antagonist of D-alanine [152]. Cycloserine inhibits the alanine racemase Alr (Rv3423c), which converts L-alanine to D-alanine, and the D-Ala:D-Ala ligase DdLA (Rv2981c) [153] preventing the integration of alanine into the pentapeptide core of the peptidoglycan. In _M. tuberculosis_, DdLA is thought to be the primary target of cycloserine [154; 155; 156]. _Resistance._ D-cycloserine-resistant _M. tuberculosis_ mutants were isolated as early as 1957 in TB patients treated with cycloserine [157]. Cycloserine resistance has been associated with mutations in the genes encoding the alanine transporter CycA (Rv1704c), the L-alanine dehydrogenase Ald (Rv2780) and the alanine racemase Alr. A Gly122 Ser mutation in _cycA_ is present in the naturally cycloserine-resistant _M. bovis_ BCG vaccine strain [158]. Complementation of BCG with a cosmid containing _M. tuberculosis__cycA_ renders BCG more susceptible to cycloserine than the parental strain leading the authors to conclude that _cycA_ may be a factor in cycloserine resistance in BCG [158]. [PERSON] and colleagues demonstrated that deletion of _ald_ increased the resistance to cycloserine 2-fold in _M. tuberculosis_, while complementation of the _ald_ mutant with a plasmid expressing _M. tuberculosis__ald_ only partially restored cycloserine susceptibility. Notably, complementation of BCG with the _ald_ plasmid did not alter the strain resistance to cycloserine [159]. Mutations in _altr_ (M319T, Y364D, R373L and c-8t in the promoter region) have been identified in XDR TB strains isolated from TB patients treated with cycloserine [160]. Further, the clinical isolate with the R373L mutation in _altr_ also contained a deletion in _ald_. In an in vitro experiment, 18 cycloserine-resistant mutants were obtained by culturing _M.