title: Reactive dirty fragments: implications for tuberculosis drug discovery.
abstract: Reactive multi-target fragments, old synthetic antimycobacterials that are activated inside Mycobacterium tuberculosis bacilli and are smaller than the usual drug-like, single-target molecules, represent critical components of current tuberculosis chemotherapies. Recent studies showed that para-aminosalicylic acid is recognized as a substrate by dihydropteroate synthase and poisons the downstream folate pathway. Pyrazinamide, a key relapse-reducing drug, is metabolized by an amidase and the reaction product interferes with trans-translation, membrane potential and other targets. However, the mechanism of action of pyrazinamide remains ill-defined and needs to be understood to rationally approach treatment shortening. The success of small dirty drugs and prodrugs suggests that fragment-based whole cell screens should be re-introduced in our current antimycobacterial drug discovery efforts.
authors: Antibacterial Drug Discovery Laboratory, Department of Microbiology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, 5 Science Drive 2, Block MD4A, Singapore 117597, Republic of Singapore.
authors: Pooja
authors: P
authors: Gopal
authors: Antibacterial Drug Discovery Laboratory, Department of Microbiology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, 5 Science Drive 2, Block MD4A, Singapore 117597, Republic of Singapore. Electronic address: thomas_dick@nuhs.edu.sg.
authors: Thomas
authors: T
authors: Dick
mesh_terms: D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D055808:Drug Discovery; D024881:Drug Resistance, Bacterial; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D011718:Pyrazinamide / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents; D011718:Pyrazinamide