# Mycobacterial Cell Wall: A Source of Successful Targets for Old and New Drugs
###### Abstract  
Eighty years after the introduction of the first antituberculosis (TB) drug, the treatment of drug-susceptible TB remains very cumbersome, requiring the use of four drugs (isoniazid, rifampicin, ethambutol and pyrazinamide) for two months followed by four months on isoniaizid and rifampicin. Two of the drugs used in this \"short\"-course, six-month chemotherapy, isoniaizid and ethambutol, target the mycobacterial cell wall. Disruption of the cell wall structure can enhance the entry of other TB drugs, resulting in a more potent chemotherapy. More importantly, inhibition of cell wall components can lead to mycobacterial cell death. The complexity of the mycobacterial cell wall offers numerous opportunities to develop drugs to eradicate _Mycobacterium tuberculosis_, the causative agent of TB. In the past 20 years, researchers from industrial and academic laboratories have tested new molecules to find the best candidates that will change the face of TB treatment: drugs that will shorten TB treatment and be efficacious against active and latent, as well as drug-resistant TB. Two of these new TB drugs block components of the mycobacterial cell wall and have reached phase 3 clinical trial. This article reviews TB drugs targeting the mycobacterial cell wall in use clinically and those in clinical development. tuberculosis; discovery; mode of action; drug resistance; toxicity; target +
Footnote †: journal: Medical  
The first drug against the etiologic agent of TB, _Mycobacterium tuberculosis_, was streptomycin, isolated from the soil bacterium _Streptomyces griseus_ and shown to have activity against _M. tuberculosis_ in 1944 [8, 9]. Streptomycin was tested on a 21-year-old woman with advanced pulmonary TB and gave \"impressive therapeutic effects\" [10, 11]. Unfortunately, resistance to streptomycin developed quickly [12, 13]. In 1946, [PERSON] published the discovery of the antimycobacterial activity of para-aminosalicylic acid (PAS) in vitro, in guinea pigs and in TB patients [14]. The addition of PAS to streptomycin treatment drastically reduced the emergence of streptomycin-resistant strains in TB patients but did not abolish it [15]. It would take the introduction of a new TB drug, isoniazid (INH), in 1952 to achieve a successful treatment for TB [16]. INH is one of the most effective drugs against _M. tuberculosis_, which is still used to this day to treat active and latent _M. tuberculosis_ infections. INH is part of a four-drug regimen (INH, rifampicin (RIF), ethambitol (EMB) and pyrazinamide (PZA)) to treat drug-susceptible _M. tuberculosis_ infection. While RIF targets the RNA polymerase RpoB and PZA's mechanism of action is still unclear, INH and EMB target the mycobacterial cell wall. The _M. tuberculosis_ cell wall has an intricate and unique structure composed of a thick peptidoglycan layer and an outer membrane made up mostly of various lipopolysaccharidesaccharides and fatty acids with imbedded glycolipids and wax esters. This lipid-rich cell wall forms a low-permeability barrier that protects _M. tuberculosis_ against most antibiotics. This is one of the many challenges facing TB drug development and the main reason drug target-based screening has been rather unsuccessful [17, 18]. Bacteria require an intact cell membrane in order to survive; therefore, the biosynthesis of cell wall components could be considered a weakness to exploit with new and more potent drugs. The ever-expanding threat of drug resistance should motivate greater alacrity in developing these new therapies. Global drug surveillance data from the World Health Organization indicates that in 2018, half a million people were infected with rifampicin- or multidrug-resistant (MDR) TB, and 6% of them had extensively drug-resistant (XDR) TB [19]. While an MDR _M. tuberculosis_ strain is \"only\" resistant to INH and RIF, an XDR strain is resistant to at least five TB drugs (INH, RIF and three second-line TB drugs).