**4. Conclusions**

reomycin resistance because the unmethylated ribosome is insensitive to the drug [81, 86, 88]. The identified mechanism of capreomycin resistance on the basis of in vitro selected mutants has found that *tlyA* mutations were common [80, 86] whereas infrequent in clini‐

Ethionamide (ETH, 2-ethylisonicotinamide) is a derivative of isonicotinic acid and has been used as an antituberculosis agent since 1956. The MICs of ETH for *M. tuberculosis* are 0.5–2 μg/ ml in liquid medium, 2.5–10 μg/ml in 7H11 agar, and 5–20 μg/ml in LJ medium. Ethionamide and the similar drug prothionamide (PTH, 2-ethyl-4-pyridinecarbothioamide) act as prodrugs, like isoniazid. Which is activated by EtaA/EthA (a mono-oxygenase) [90, 91] and inhibits the same target as INH, the InhA of the mycolic acid synthesis pathway [92]. Once delivered into the bacterial cell, ethionamide undergoes several changes. Its sulfo group is oxidized by flavin monooxygenase, and the drug is then converted to 2-ethyl-4-aminopyridine. The intermediate products formed before 2-ethyl-4-aminopyridine seem to be toxic to mycobac‐ teria, but their structures are unknown (may be highly unstable compounds). Mutants resistant to ethionamide are cross-resistant to prothionamide. ETH frequently causes gastrointestinal side effects, such as abdominal pain, nausea, vomiting and anorexia. It can cause hypothyr‐

*p-*Amino salicylic acid (PAS) was one of the first antibiotics to show anti-TB activity and was used to treat TB in combination with isoniazid and streptomycin [93]. Later, with the discovery of other more potent drugs including rifampicin, its use in first line regimens was discontinued. PAS is still useful as part of a treatment regimen for XDR TB although its benefit is limited and it is extremely toxic. Thymidylate synthase A, encoded by *thyA*, an enzyme involved in the biosynthesis of thymine, has been proposed recently as the target of PAS in *M. bovis* BCG [94]. Most common mutation in *thyA* was Thr202Ala, though few susceptible isolates also showed the same mutation [95]. However, its mechanism of action was never clearly elucidated. The most common adverse reactions associated with PAS are gastrointestinal disturbances.

Cycloserine (CS) is an antibiotic that is used to treat TB. The exact mechanism of action of cycloserine is unknown, but it is thought to prevent the tuberculosis bacteria from making substances called peptidoglycans, which are needed to form the bacterial cell wall. This results in the weakening of bacteria's cell wall, which then kills the bacteria. Cycloserine possesses high gastric tolerance (compared with the other drugs) and lacks cross-resistance to other compounds. But it causes adverse psychiatric effects; [96, 97] which is its main drawback. So, psychiatric interrogation is necessary before prescribing cycloserine drug. Cycloserine is one of the cornerstones of treatment for MDR and XDR tuberculosis [96, 97, 98]. Terizidone (a combination of two molecules of cycloserine) might be less toxic [96, 97], although studies of

cal isolates of *M. tuberculosis* [79, 80].

170 Tuberculosis - Current Issues in Diagnosis and Management

oidism, particularly if it is used with *para*-aminosalicyclic acid.

**3.3. Ethionamide/prothionamide**

**3.4.** *p-***Amino salicylic acid**

**3.5. Cycloserine**

this drug are scarce.

Despite all the advances made in the treatment and management, TB still remains as one of the main public health problems that have plagued mankind for millennia. The challenges posed by *M. tuberculosis* infection, through its interaction with the immune system and its mechanisms for evasion, require many more breakthroughs to make a significant impact on the worldwide tuberculosis problem. The introduction of MDR and XDR strains of *M. tuberculosis* poses several problems in mycobacterial genetics and phthisiotherapy. Among the response priorities, rapid detection of anti-tuberculosis drug resistance, use of appropriate regimens for treatment, and new drug development are of paramount importance. However, regarding the dynamics of TB transmission, and also in view of rational development of new anti-TB drugs, it is extremely important to extend our knowledge on the molecular basis of drug resistance and all its complexity. It is necessary to clarify the association between specific mutations and the development of MDR-TB or the association between drug resistance and fitness. This would allow better evaluation of the transmission dynamics of resistant strains and more accurate prediction of a future disease scenario. Adequate monitoring of drug resistance, especially MDR/XDR-TB in new patients and its transmission, molecular charac‐ terization of the drug-resistant strains, and analysis of patients' immune status and genetic susceptibility are also needed to address the problem of the fitness, virulence and transmissi‐ bility of drug-resistant *M. tuberculosis* strains.
