title: Incorporation of triphenylphosphonium functionality improves the inhibitory properties of phenothiazine derivatives in Mycobacterium tuberculosis.
abstract: Tuberculosis (TB) is a difficult to treat disease caused by the bacterium Mycobacterium tuberculosis. The need for improved therapies is required to kill different M. tuberculosis populations present during infection and to kill drug resistant strains. Protein complexes associated with energy generation, required for the survival of all M. tuberculosis populations, have shown promise as targets for novel therapies (e.g., phenothiazines that target type II NADH dehydrogenase (NDH-2) in the electron transport chain). However, the low efficacy of these compounds and their off-target effects has made the development of phenothiazines as a therapeutic agent for TB limited. This study reports that a series of alkyltriphenylphosphonium (alkylTPP) cations, a known intracellular delivery functionality, improves the localization and effective concentration of phenothiazines at the mycobacterial membrane. AlkylTPP cations were shown to accumulate at biological membranes in a range of bacteria and lipophilicity was revealed as an important feature of the structure-function relationship. Incorporation of the alkylTPP cationic function significantly increased the concentration and potency of a series of phenothiazine derivatives at the mycobacterial membrane (the site of NDH-2), where the lead compound 3a showed inhibition of M. tuberculosis growth at 0.5μg/mL. Compound 3a was shown to act in a similar manner to that previously published for other active phenothiazines by targeting energetic processes (i.e., NADH oxidation and oxygen consumption), occurring in the mycobacterial membrane. This shows the enormous potential of alkylTPP cations to improve the delivery and therefore efficacy of bioactive agents targeting oxidative phosphorylation in the mycobacterial membrane.
authors.affiliation: Department of Microbiology & Immunology, University of Otago, PO Box 56, Dunedin 9054, New Zealand.
authors.forename: Elyse A
authors.initials: EA
authors.lastname: Dunn
authors.affiliation: Department of Chemistry, University of Otago, PO Box 56, Dunedin 9054, New Zealand.
authors.forename: Marina
authors.initials: M
authors.lastname: Roxburgh
authors.affiliation: Department of Chemistry, University of Otago, PO Box 56, Dunedin 9054, New Zealand.
authors.forename: Lesley
authors.initials: L
authors.lastname: Larsen
authors.affiliation: Department of Chemistry, University of Otago, PO Box 56, Dunedin 9054, New Zealand.
authors.forename: Robin A J
authors.initials: RA
authors.lastname: Smith
authors.affiliation: Department of Microbiology & Immunology, University of Otago, PO Box 56, Dunedin 9054, New Zealand.
authors.forename: Alexander D
authors.initials: AD
authors.lastname: McLellan
authors.affiliation: Department of Microbiology & Immunology, University of Otago, PO Box 56, Dunedin 9054, New Zealand.
authors.forename: Adam
authors.initials: A
authors.lastname: Heikal
authors.affiliation: MRC Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Murphy
authors.affiliation: Department of Microbiology & Immunology, University of Otago, PO Box 56, Dunedin 9054, New Zealand. Electronic address: gregory.cook@otago.ac.nz.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Cook
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000494:pharmacology*; D010640:Phenothiazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D009943:Organophosphorus Compounds; D010640:Phenothiazines; C031637:phenothiazine
keywords: Alkyltriphenylphosphonium cation; Drug delivery; Energy generation; Mycobacteria