combination therapy to prevent selection of drug resistance and relapse due to persisting bacilli [29]. The development of rifampicin was a major breakthrough because it allowed treatment duration to be shortened to 9 months. The discovery of ethambutol in the 1960s and the introduction of pyrazinamide at a lower dose led to the currently used 6-month regimen. Table 1 summarises the main advances in shortening treatment duration. Currently, there are 21 drugs from several classes available for the treatment of TB. Figure 2 presents the mechanisms of action of the currently used anti-TB drugs. Rifamycins (rifampicin, rifabutin, rifapentine) block the RNA polymerase enzyme and thus inhibit gene transcription of mRNA [32]. Unlike rifamycins which are used to treat other bacterial infections, the antimicrobial spectrum of isoniazid is selective for mycobacteria. Isoniazid’s exact mechanism of action is not completely understood yet. It blocks cell wall synthesis by interfering in mycolic acid synthesis. Isoniazid is converted by a catalase peroxidase within M. tuberculosis into an active metabolite able to inhibit inhA, an enzyme necessary to bacterial survival [33]. Thioamide drugs, ethionamide and prothionamide also seem to inhibit inhA [34]. Pyrazinamide interferes with multiple mechanisms such as energy production, intracellular acidification and plasma membrane disruption [28, 35]. Ethambutol blocks arabinosyltransferases embA, embB, and embC, enzymes involved in the generation of arabinogalactan, a mycobacterial cell wall constituent [18]. Fluoroquinolones (levofloxacin and moxifloxacin) increase levels of DNA breaks produced by M. tuberculosis DNA gyrase, a type II topoisomerase necessary to shape double-stranded DNA [36]. Aminoglycosides (amikacin, capreomycin, kanamycin, streptomycin) and oxazolidinones (linezolid) bind to the mycobacterial ribosome and inhibit protein synthesis [37, 38]. Para-aminosalicylic acid (PAS) disrupts folate metabolism through competitive binding with dihydrofolate reductase, thus stopping the growth of M. tuberculosis [39]. Bedaquiline inhibits the mycobacterial adenosine 5′-triphosphate (ATP) synthase [40]. Delamanid interferes in the synthesis of methoxymycolate and ketomycolate [41]. Pretomanid inhibits the oxidation of hydroxymycolate to ketomycolate [42]. Terizidone and cycloserine inhibit L -alanine racemase and D -alanine ligase involved in cell wall synthesis [43]. Clofazimine affects intracellular redox cycling and membrane destabilisation [44]. Carbapenems, though weak substrates for M. tuberculosis β-lactamase, are efficient when associated with clavulanate which inactivates the β-lactamase encoded by the blaC gene [28, 45]. TABLE 1 Main steps in the development of treatment protocols for drug-susceptible TB Year [Ref.] Drug(s) Consequence 1948 [26] Streptomycin First anti-TB antibiotic therapy [29] Monotherapy leads to drug resistance and relapses 1951 [29] Streptomycin+PASstreptomycin Drug combination prevents drug resistance 1962 [30] Isoniazid+streptomycin+PAS First anti-TB regimen: 18 months’ treatment 1970s [30] Isoniazid+rifampicin+ethambutol Treatment length divided by 2: 9 months 1980s [30] Isoniazid+rifampicin+pyrazinamide +ethambutol Current treatment of drug-susceptible TB: 6 months 2021 [31] Isoniazid+rifapentin+moxifloxacin +pyrazinamide 4-month regimen PAS: para-aminosalicylic acid. 120 https://doi.org/10.1183/2312508X.10024622 ERS MONOGRAPH |THE CHALLENGE OF TB IN THE 21ST CENTURY