Thiophene-4

Thiophene-4 (TP4) is an inhibitor of polyketide synthase 13 (Pks13), which plays a critical role in the biosynthesis of mycolic acid, an essential component of the cell wall in M. tuberculosis, and is a potential new target for tuberculosis treatment. TP4 inhibits FadD32-dependent loading of the mycolic acid precursor meromycoloyl chain onto acyl carrier protein (ACP) domains located at the N terminus of Pks13, preventing synthesis of mycolic acid and resulting in mycobacterial cell death. TP4 bacteriosidal activity is equivalent to treatment with the first-line drug isoniazid, and enhances its activity, but is less likely to cause resistance. The minimal inhibitory concentration (MIC) values of TP4 against drug-susceptible multidrug-resistant M. tuberculosis strains is approximately 500 nM.