title: Indoleamides are active against drug-resistant Mycobacterium tuberculosis.
abstract: Responsible for nearly two million deaths each year, the infectious disease tuberculosis remains a serious global health challenge. The emergence of multidrug- and extensively drug-resistant strains of Mycobacterium tuberculosis confounds control efforts, and new drugs with novel molecular targets are desperately needed. Here we describe lead compounds, the indoleamides, with potent activity against both drug-susceptible and drug-resistant strains of M. tuberculosis by targeting the mycolic acid transporter MmpL3. We identify a single mutation in mmpL3, which confers high resistance to the indoleamide class while remaining susceptible to currently used first- and second-line tuberculosis drugs, indicating a lack of cross-resistance. Importantly, an indoleamide derivative exhibits dose-dependent antimycobacterial activity when orally administered to M. tuberculosis-infected mice. The bioavailability of the indoleamides, combined with their ability to kill tubercle bacilli, indicates great potential for translational developments of this structure class for the treatment of drug-resistant tuberculosis.
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University School of Medicine, 1550 Orleans Street, CRB2 Suite 103, Baltimore, Maryland 21231, USA.
authors.forename: Shichun
authors.initials: S
authors.lastname: Lun
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University School of Medicine, 1550 Orleans Street, CRB2 Suite 103, Baltimore, Maryland 21231, USA.
authors.forename: Haidan
authors.initials: H
authors.lastname: Guo
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Room 531, Chicago, Illinois 60612, USA.
authors.forename: Oluseye K
authors.initials: OK
authors.lastname: Onajole
authors.affiliation: 1] Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Room 531, Chicago, Illinois 60612, USA [2].
authors.forename: Marco
authors.initials: M
authors.lastname: Pieroni
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Room 531, Chicago, Illinois 60612, USA.
authors.forename: Hendra
authors.initials: H
authors.lastname: Gunosewoyo
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Room 531, Chicago, Illinois 60612, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.affiliation: 1] Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Room 531, Chicago, Illinois 60612, USA [2].
authors.forename: Suresh K
authors.initials: SK
authors.lastname: Tipparaju
authors.affiliation: 1] Center for Tuberculosis Research, Johns Hopkins University School of Medicine, 1550 Orleans Street, CRB2 Suite 103, Baltimore, Maryland 21231, USA [2] KwaZulu-Natal Research Institute for Tuberculosis and HIV, 719 Umbilo Road, Durban 4001, South Africa.
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Ammerman
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Room 531, Chicago, Illinois 60612, USA.
authors.forename: Alan P
authors.initials: AP
authors.lastname: Kozikowski
authors.affiliation: 1] Center for Tuberculosis Research, Johns Hopkins University School of Medicine, 1550 Orleans Street, CRB2 Suite 103, Baltimore, Maryland 21231, USA [2] KwaZulu-Natal Research Institute for Tuberculosis and HIV, 719 Umbilo Road, Durban 4001, South Africa [3] Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, Maryland 20815, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Bishai
mesh_terms: D000818:Animals; D027321:Anion Transport Proteins / Q000235:genetics; D000995:Antitubercular Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects / Q000235:genetics; D005260:Female; D007211:Indoles / Q000737:chemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D058990:Molecular Targeted Therapy; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D020641:Polymorphism, Single Nucleotide; D018088:Tuberculosis, Multidrug-Resistant / Q000382:microbiology; D014709:Vero Cells / Q000187:drug effects / Q000382:microbiology
chemical_list: D027321:Anion Transport Proteins; D000995:Antitubercular Agents; D001426:Bacterial Proteins; D007211:Indoles