New anti-tuberculosis drugs with novel mechanisms of action.
It is estimated that a third of the world's population is currently infected with tuberculosis, leading to 1.6 million deaths annually. The current drug regimen is 40 years old and takes 6-9 months to administer. In addition, the emergence of drug resistant strains and HIV co-infection mean that there is an urgent need for new anti-tuberculosis drugs. The twenty-first century has seen a revival in research and development activity in this area, with several new drug candidates entering clinical trials. This review considers new potential first-line anti-tuberculosis drug candidates, in particular those with novel mechanisms of action, as these are most likely to prove effective against resistant strains. A brief overview of current first-line and recent drugs (such as fluoroquinolones, rifampicin and isoniazid analogues) is initially presented. This is followed by a description of structure-activity relationships, in vitro and in vivo activity, pharmacokinetics, mechanism of action, combination regimens and clinical trials of the new drug candidates SQ109, PA-824, OPC-67683, TMC207 and others.
Rivers
Emma C
EC
Western Australian Biomedical Research Institute, School of Pharmacy and School of Biomedical Sciences, Curtin University of Technology, GPO Box U1987, Perth WA 6845, Australia.
Mancera
Ricardo L
RL
D000218:Adamantane / Q000031:analogs & derivatives / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D000995:Antitubercular Agents / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D064687:Diarylquinolines; D015195:Drug Design; D024901:Drug Resistance, Multiple, Bacterial; D005029:Ethylenediamines / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D009593:Nitroimidazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D010080:Oxazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D011804:Quinolines / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy*
D000995:Antitubercular Agents; D064687:Diarylquinolines; D005029:Ethylenediamines; C506841:N-geranyl-N'-(2-adamantyl)ethane-1,2-diamine; D009593:Nitroimidazoles; C516022:OPC-67683; D010080:Oxazoles; D011804:Quinolines; C410767:pretomanid; C493870:bedaquiline; D000218:Adamantane