Reactive dirty fragments: implications for tuberculosis drug discovery

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.