title: Multitarget drug discovery for tuberculosis and other infectious diseases.
abstract: We report the discovery of a series of new drug leads that have potent activity against Mycobacterium tuberculosis as well as against other bacteria, fungi, and a malaria parasite. The compounds are analogues of the new tuberculosis (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 biosynthesis, 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, as well as very low rates of spontaneous drug resistance. Several targets are absent in humans but are present in other bacteria, as well as in malaria parasites, whose growth is also inhibited.
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign , 600 South Mathews Avenue, Urbana, Illinois 61801, United States.
authors.forename: Kai
authors.initials: K
authors.lastname: Li
authors.forename: Lici A
authors.initials: LA
authors.lastname: Schurig-Briccio
authors.forename: Xinxin
authors.initials: X
authors.lastname: Feng
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Upadhyay
authors.forename: Venugopal
authors.initials: V
authors.lastname: Pujari
authors.forename: Benoit
authors.initials: B
authors.lastname: Lechartier
authors.forename: Fabio L
authors.initials: FL
authors.lastname: Fontes
authors.forename: Hongliang
authors.initials: H
authors.lastname: Yang
authors.forename: Guodong
authors.initials: G
authors.lastname: Rao
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.forename: Anmol
authors.initials: A
authors.lastname: Gulati
authors.forename: Joo Hwan
authors.initials: JH
authors.lastname: No
authors.forename: Giovana
authors.initials: G
authors.lastname: Cintra
authors.forename: Shannon
authors.initials: S
authors.lastname: Bogue
authors.forename: Yi-Liang
authors.initials: YL
authors.lastname: Liu
authors.forename: Katie
authors.initials: K
authors.lastname: Molohon
authors.forename: Peter
authors.initials: P
authors.lastname: Orlean
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Mitchell
authors.forename: Lucio
authors.initials: L
authors.lastname: Freitas-Junior
authors.forename: Feifei
authors.initials: F
authors.lastname: Ren
authors.forename: Hong
authors.initials: H
authors.lastname: Sun
authors.forename: Tong
authors.initials: T
authors.lastname: Jiang
authors.forename: Yujie
authors.initials: Y
authors.lastname: Li
authors.forename: Rey-Ting
authors.initials: RT
authors.lastname: Guo
authors.forename: Stewart T
authors.initials: ST
authors.lastname: Cole
authors.forename: Robert B
authors.initials: RB
authors.lastname: Gennis
authors.forename: Dean C
authors.initials: DC
authors.lastname: Crick
authors.forename: Eric
authors.initials: E
authors.lastname: Oldfield
mesh_terms: D000890:Anti-Infective Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000995:Antitubercular Agents / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D055808:Drug Discovery; D005260:Female; D005658:Fungi / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology; D026901:Membrane Transport Proteins / Q000378:metabolism*; D008958:Models, Molecular; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D010963:Plasmodium falciparum / Q000187:drug effects; D013329:Structure-Activity Relationship; D014376:Tuberculosis / Q000188:drug therapy / Q000382:microbiology; D014407:Tumor Cells, Cultured
chemical_list: D000890:Anti-Infective Agents; D000970:Antineoplastic Agents; D000995:Antitubercular Agents; D026901:Membrane Transport Proteins