The past, present and future of tuberculosis treatment

<p indent="0mm">Tuberculosis (TB) is an ancient infectious disease with high morbidity and mortality before the advent of effective drug therapy. In the past 100 years, the discovery of revolutionary anti-TB drugs such as streptomycin, isoniazid, pyrazinamide, ethambutol and rifampicin, along with drug combination treatment, has greatly improved TB control globally. As anti-TB drugs were widely used, multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of <italic>Mycobacterium tuberculosis</italic> emerged due to acquired genetic mutations, which presents a major problem for effective treatment. Genes associated with drug resistance have been identified, including <italic>katG</italic> mutations in isoniazid resistance, and <italic>rpoB</italic> mutations in rifampin resistance, <italic>pncA</italic> mutations in pyrazinamide resistance, and <italic>gyrA</italic> mutations in quinolone resistance. The major mechanisms of drug resistance include loss of enzyme activity in prodrug activation, drug target alteration, overexpression of drug target, and overexpression of efflux pump. During the disease process, <italic>Mycobacterium</italic> <italic>tuberculosis</italic> resides in different microenvironments including exposure to acid pH, low oxygen, reactive oxygen species and anti-TB drugs, which can facilitate the development of non-replicating persisters and promote bacterial survival. The mechanisms of persister formation may include toxin-antitoxin (TA) modules, DNA protection and repair, protein degradation such as trans-translation, efflux, and altered metabolism. In recent years, the use of new anti-TB drugs, repurposed drugs, and their drug combinations has greatly improved treatment outcomes in patients with both drug-susceptible TB and MDR/XDR-TB. The importance of developing more effective drugs targeting persisters of <italic>Mycobacterium</italic> <italic>tuberculosis</italic> is emphasized, and host-directed therapeutics, using both conventional drugs and herbal medicines for more effective TB treatment should also be attempted. In this article, we review historical aspects of the research on anti-TB drugs and discuss the current understanding and treatments of drug resistant and persistent tuberculosis, in order to inform future therapeutic development.