title: Amphiphilic Indole Derivatives as Antimycobacterial Agents: Structure-Activity Relationships and Membrane Targeting Properties.
abstract: Antibacterials that disrupt cell membrane function have the potential to eradicate "persister" organisms and delay the emergence of resistance. Here we report the antimycobacterial activities of 4-fluoro and 6-methoxyindoles bearing a cationic amphiphilic motif represented by a lipophilic n-octyl side chain at position 1 and a positively charged azepanyl or 1,4-dioxa-8-azaspiro[4.5]decane moiety at position 3. These analogues exhibited balanced profiles of potency (Mycobacterium bovis BCG, M tuberculosis H37Rv), selective activity, solubility, and metabolic stability. Bacteriological mechanism of action investigations on a representative analogue revealed cell membrane permeabilization and depolarization in M bovis BCG. These membrane-related changes preceded cell death indicating that the loss in membrane integrity was not an epiphenomenon. Bactericidal activity was observed against both growing and nongrowing mycobacterial cultures. The analogue also upregulated cell envelope stress-inducible promoters piniBAC and pclgR, implicating the involvement of envelope-related targets in its mode of action.
authors.affiliation: Department of Pharmacy and ‡Department of Microbiology and Immunology, National University of Singapore , Singapore 117543, Singapore.
authors.forename: Tianming
authors.initials: T
authors.lastname: Yang
authors.affiliation: Department of Pharmacy and ‡Department of Microbiology and Immunology, National University of Singapore , Singapore 117543, Singapore.
authors.forename: Wilfried
authors.initials: W
authors.lastname: Moreira
authors.affiliation: Department of Pharmacy and ‡Department of Microbiology and Immunology, National University of Singapore , Singapore 117543, Singapore.
authors.forename: Samuel Agyei
authors.initials: SA
authors.lastname: Nyantakyi
authors.affiliation: Department of Pharmacy and ‡Department of Microbiology and Immunology, National University of Singapore , Singapore 117543, Singapore.
authors.forename: Huan
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Pharmacy and ‡Department of Microbiology and Immunology, National University of Singapore , Singapore 117543, Singapore.
authors.forename: Dinah Binte
authors.initials: DB
authors.lastname: Aziz
authors.affiliation: Department of Pharmacy and ‡Department of Microbiology and Immunology, National University of Singapore , Singapore 117543, Singapore.
authors.forename: Mei-Lin
authors.identifier: 0000-0003-4757-3343
authors.initials: ML
authors.lastname: Go
authors.affiliation: Department of Pharmacy and ‡Department of Microbiology and Immunology, National University of Singapore , Singapore 117543, Singapore.
authors.forename: Thomas
authors.identifier: 0000-0002-9604-9452
authors.initials: T
authors.lastname: Dick
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D005260:Female; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009163:Mycobacterium bovis / Q000187:drug effects* / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents; D007211:Indoles