title: Structure-activity relationships at the 5-position of thiolactomycin: an intact (5R)-isoprene unit is required for activity against the condensing enzymes from Mycobacterium tuberculosis and Escherichia coli.
abstract: Thiolactomycin inhibits bacterial cell growth through inhibition of the beta-ketoacyl-ACP synthase activity of type II fatty acid synthases. The effect of modifications of the 5-position isoprenoid side chain on both IC(50) and MIC were determined. Synthesis and screening of a structurally diverse set of 5-position analogues revealed very little tolerance for substitution in purified enzyme assays, but a few analogues retained MIC, presumably through another target. Even subtle modifications such as reducing one or both double bonds of the diene were not tolerated. The only permissible structural modifications were removal of the isoprene methyl group or addition of a methyl group to the terminus. Cocrystallization of these two inhibitors with the condensing enzyme from Escherichia coli revealed that they retained the TLM binding mode at the active site with reduced affinity. These results suggest a strict requirement for a conjugated, planar side chain inserting within the condensing enzyme active site.
authors.affiliation: Tuberculosis Research Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland 20852, USA.
authors.forename: Pilho
authors.initials: P
authors.lastname: Kim
authors.forename: Yong-Mei
authors.initials: YM
authors.lastname: Zhang
authors.forename: Gautham
authors.initials: G
authors.lastname: Shenoy
authors.forename: Quynh-Anh
authors.initials: QA
authors.lastname: Nguyen
authors.forename: Helena I
authors.initials: HI
authors.lastname: Boshoff
authors.forename: Ujjini H
authors.initials: UH
authors.lastname: Manjunatha
authors.forename: Michael B
authors.initials: MB
authors.lastname: Goodwin
authors.forename: John
authors.initials: J
authors.lastname: Lonsdale
authors.forename: Allen C
authors.initials: AC
authors.lastname: Price
authors.forename: Darcie J
authors.initials: DJ
authors.lastname: Miller
authors.forename: Ken
authors.initials: K
authors.lastname: Duncan
authors.forename: Stephen W
authors.initials: SW
authors.lastname: White
authors.forename: Charles O
authors.initials: CO
authors.lastname: Rock
authors.forename: Clifton E
authors.initials: CE
authors.lastname: Barry
authors.forename: Cynthia S
authors.initials: CS
authors.lastname: Dowd
mesh_terms: D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / Q000037:antagonists & inhibitors*; D002070:Butadienes / Q000737:chemistry*; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development; D045782:Hemiterpenes / Q000737:chemistry*; D008024:Ligands; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development; D010420:Pentanes / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D002070:Butadienes; D045782:Hemiterpenes; D008024:Ligands; D010420:Pentanes; D013876:Thiophenes; C005059:isoprene; C035068:thiolactomycin; D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase