Tuberculosis — The Development of New MDR-TB Drugs
Authors: Jarmila Vinšová and Martin Krátký
Abstract: The aim of this review is to outline the recent advances in the development of new multidrug-resistant tuberculosis (MDR-TB) drugs. The emergence of resistance to antituberculosis drugs, particularly of MDR-TB and more recently XDR-TB, has become a major public health problem. The current treatment regimen has several disadvantages, i.e. long treatment period (DOTS takes minimum 6 months) during which tubercle bacilli mutant becomes resistant to one or more drugs; side effects of the used drugs; coinfection of HIV/AIDS. The emergence of MDR-TB has made many currently available anti-TB drugs ineffective. Sleeping latent forms of mutant bacilli resistant to common anti-TB drugs create the risk of epidemic for the new generation. Therefore, there is an urgent need to identify new drug targets and to find novel chemical structures active especially against MDR-TB. In general, drug resistance mechanisms in Mycobacterium tuberculosis are caused by mutations in chromosomal genes. It includes target modifications, barrier mechanism, inactivation or activation of enzymes, mutation in the genes such as inhA, rpoB, rpsL, rrs, emrB and gyrA, responsible for INH, RIF, STM, EMB and quinolone resistances. Some novel targets as an essential cell division protein (FtsZ), ATP-synthase target, isocitrate lyase, targeting P450 enzymes, etc., are presented. The research of novel MDR potential drugs follows six main strategies: a) structure modification of known compounds (INH, RIF, PZA, ETH, EMB, quinolones); b) new leads with novel mechanism of action (linezolid, TMC207, PA-824, OPC-67683, BM212, SQ109, FAS20013, LL-3858); c) novel drug targets, i.e. cell wall biosynthesis (mycolic acid synthesis, protein synthesis, arabinogalactan and peptidoglycan biosynthesis inhibitors) or other novel targets like enzymes; d) investigation of “non-antituberculous” drugs; e) testing of newly prepared synthetic compounds without known mechanism of action; f) screening of natural products, determination and isolation of active compounds.