MECHANISM OF ACTION OF MEMBRANE TARGETING CATIONIC AMPHIPHILIC INDOLE ANTIMYCOBACTERIALS

Abstract

Drug-tolerant persisters render tuberculosis treatment lengthy and cause latent infection. To eliminate persisters, selective targeting of the membrane has been suggested. Here, two series of membrane-targeting cationic amphiphilic indoles were profiled. Series Ⅰ contains a reported membrane-inserting scaffold – n-octyl indolyl Mannich base. Inclusion of an azaspiroketal motif in the Mannich base of the scaffold showed potency jump and led to the identification of the lead Ⅰ-5. Ⅰ-5 showed submicromolar potency, superior selectivity, anti-persister property, in vivo activity and membrane permeabilization. Lines of evidence from genetic, microbiological, microscopy, computational and biochemical investigations proved that potency jump of Ⅰ-5 arises from its additional targeting of MmpL3 by azaspiroketal Mannich base. Studies on Ⅰ-5 provided proof-of-concept that functional groups could be introduced in membrane-inserting scaffolds to target extra molecule(s) for pathogen-specific activity. Series Ⅱ, conjugates of indole nucleus and triphenylphosphonium cation, caused rapid and significant membrane depolarization, leading to interception of oxidative phosphorylation.