Multitarget Drug Discovery for Tuberculosis and Other Infectious Diseases

*S Supporting Information ABSTRACT: We report the discovery of a series of new drug leads that have potent activity against Mycobacterium tuber-culosis as well as against other bacteria, fungi, and a malaria parasite. The compounds are analogues of the new tuber-culosis (TB) drug SQ109 (1), which has been reported to act by inhibiting a transporter called MmpL3, involved in cell wall biosynthesis. We show that 1 and the new compounds also target enzymes involved in menaquinone biosynthesis and electron transport, inhibiting respiration and ATP biosyn-thesis, and are uncouplers, collapsing the pH gradient and membrane potential used to power transporters. The result of such multitarget inhibition is potent inhibition of TB cell growth