title: Design, synthesis, and X-ray crystallographic studies of α-aryl substituted fosmidomycin analogues as inhibitors of Mycobacterium tuberculosis 1-deoxy-D-xylulose 5-phosphate reductoisomerase.
abstract: The natural antibiotic fosmidomycin acts via inhibition of 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR), an essential enzyme in the non-mevalonate pathway of isoprenoid biosynthesis. Fosmidomycin is active on Mycobacterium tuberculosis DXR (MtDXR), but it lacks antibacterial activity probably because of poor uptake. α-Aryl substituted fosmidomycin analogues have more favorable physicochemical properties and are also more active in inhibiting malaria parasite growth. We have solved crystal structures of MtDXR in complex with 3,4-dichlorophenyl substituted fosmidomycin analogues; these show important differences compared to our previously described forsmidomycin-DXR complex. Our best inhibitor has an IC(50) = 0.15 μM on MtDXR but still lacked activity in a mycobacterial growth assay (MIC > 32 μg/mL). The combined results, however, provide insights into how DXR accommodates the new inhibitors and serve as an excellent starting point for the design of other novel and more potent inhibitors, particularly against pathogens where uptake is less of a problem, such as the malaria parasite.
authors.affiliation: Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala University, Biomedical Center, Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: Mounir
authors.initials: M
authors.lastname: Andaloussi
authors.forename: Lena M
authors.initials: LM
authors.lastname: Henriksson
authors.forename: Anna
authors.initials: A
authors.lastname: Więckowska
authors.forename: Martin
authors.initials: M
authors.lastname: Lindh
authors.forename: Christofer
authors.initials: C
authors.lastname: Björkelid
authors.forename: Anna M
authors.initials: AM
authors.lastname: Larsson
authors.forename: Surisetti
authors.initials: S
authors.lastname: Suresh
authors.forename: Harini
authors.initials: H
authors.lastname: Iyer
authors.forename: Bachally R
authors.initials: BR
authors.lastname: Srinivasa
authors.forename: Terese
authors.initials: T
authors.lastname: Bergfors
authors.forename: Torsten
authors.initials: T
authors.lastname: Unge
authors.forename: Sherry L
authors.initials: SL
authors.lastname: Mowbray
authors.forename: Mats
authors.initials: M
authors.lastname: Larhed
authors.forename: T Alwyn
authors.initials: TA
authors.lastname: Jones
authors.forename: Anders
authors.initials: A
authors.lastname: Karlén
mesh_terms: D019747:Aldose-Ketose Isomerases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D015195:Drug Design; D005578:Fosfomycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000737:chemistry; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: D000995:Antitubercular Agents; D009097:Multienzyme Complexes; D005578:Fosfomycin; C024640:fosmidomycin; D010088:Oxidoreductases; C114231:1-deoxy-D-xylulose 5-phosphate reductoisomerase; D019747:Aldose-Ketose Isomerases