title: Antimycobacterial activity of UDP-galactopyranose mutase inhibitors.
abstract: The galactofuran region of the mycobacterial cell wall consists of alternating 5- and 6-linked beta-d-galactofuranose (beta-D-Galf) residues, essential for viability. UDP-galactofuranose (UDP-Galf), the donor for Galf, is synthesised from UDP-galactopyranose (UDP-Galp) by the enzyme UDP-galactopyranose mutase (UGM), which is not found in humans, rendering it a therapeutic target. The in vitro properties, i.e. enzymatic activity, antimycobacterial activity, cellular toxicity, activity in mycobacterial-infected macrophages and activity against non-replicating persistent mycobacteria, of (4-chlorophenyl)-[1-(4-chlorophenyl)-3-hydroxy-5-methyl-1H-pyrazol-4-yl]-methanone and 3-(4-iodophenyl)-2-[4-(3,4-dichlorophenyl)-thiazol-2-ylamino]-propionic acid were studied. The former compound, a pyrazole, was an inhibitor of UGM from Mycobacterium tuberculosis and Klebsiella pneumoniae and was effective against Mycobacterium smegmatis, Mycobacterium bovis BCG and M. tuberculosis but ineffective against other bacterial strains tested. This compound showed potency against mycobacteria in infected macrophages but exhibited moderate cellular toxicity and was ineffective against non-replicating persistent mycobacteria. This is the first report of a compound both with UGM inhibitory properties and broad antimycobacterial activities. The latter compound, an aminothiazole, was active against UGM from K. pneumoniae and M. tuberculosis but was ineffective against M. bovis BCG or M. tuberculosis as well as demonstrating higher cellular toxicity. These data validate the choice of UGM as a target for active antimycobacterial therapy and confirm the pyrazole compound as a viable lead candidate.
authors.affiliation: Department of Chemistry, Simon Fraser University, Burnaby, BC, Canada V5A 1S6.
authors.forename: Silvia
authors.initials: S
authors.lastname: Borrelli
authors.forename: Wesley F
authors.initials: WF
authors.lastname: Zandberg
authors.forename: Sankar
authors.initials: S
authors.lastname: Mohan
authors.forename: Mary
authors.initials: M
authors.lastname: Ko
authors.forename: Fidel
authors.initials: F
authors.lastname: Martinez-Gutierrez
authors.forename: Sarathy Karunan
authors.initials: SK
authors.lastname: Partha
authors.forename: David A R
authors.initials: DA
authors.lastname: Sanders
authors.forename: Yossef
authors.initials: Y
authors.lastname: Av-Gay
authors.forename: B Mario
authors.initials: BM
authors.lastname: Pinto
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D019751:Intramolecular Transferases / Q000037:antagonists & inhibitors*; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D009161:Mycobacterium / Q000187:drug effects* / Q000201:enzymology; D009163:Mycobacterium bovis / Q000187:drug effects* / Q000201:enzymology; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology / Q000472:pathogenicity; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity
chemical_list: C555032:(4-chlorophenyl)-(1-(4-chlorophenyl)-3-hydroxy-5-methyl-1H-pyrazol-4-yl)methanone; C555033:3-(4-iodophenyl)-2-(4-(3,4-dichlorophenyl)thiazol-2-ylamino)propionic acid; D000900:Anti-Bacterial Agents; D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D013844:Thiazoles; D010649:Phenylalanine; D019751:Intramolecular Transferases; C098051:UDP-galactopyranose mutase