title: Discovery of novel bacterial elongation condensing enzyme inhibitors by virtual screening.
abstract: The elongation condensing enzymes in the bacterial fatty acid biosynthesis pathway represent desirable targets for the design of novel, broad-spectrum antimicrobial agents. A series of substituted benzoxazolinones was identified in this study as a novel class of elongation condensing enzyme (FabB and FabF) inhibitors using a two-step virtual screening approach. Structure activity relationships were developed around the benzoxazolinone scaffold showing that N-substituted benzoxazolinones were most active. The benzoxazolinone scaffold has high chemical tractability making this chemotype suitable for further development of bacterial fatty acid synthesis inhibitors.
authors.affiliation: Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Joshua B
authors.initials: JB
authors.lastname: Parsons
authors.affiliation: Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Rajendra
authors.initials: R
authors.lastname: Tangallapally
authors.affiliation: Department of Structural Biology, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Weixing
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Charles O
authors.initials: CO
authors.lastname: Rock
authors.affiliation: Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: richard.lee@stjude.org.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Lee
mesh_terms: D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001583:Benzoxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects*; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054889:Fatty Acid Synthase, Type II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D001583:Benzoxazoles; D004791:Enzyme Inhibitors; D029968:Escherichia coli Proteins; D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase; C490369:FabB protein, E coli; D054889:Fatty Acid Synthase, Type II
keywords: Antibiotics; Condensing enzymes; Fatty acid synthesis; Virtual screening
references.citation: Curr Opin Microbiol. 2011 Oct;14(5):544-9
references.pmid: 21862391
references.citation: Appl Microbiol Biotechnol. 2002 May;58(6):695-703
references.pmid: 12021787
references.citation: J Chem Inf Model. 2013 Mar 25;53(3):560-72
references.pmid: 23432621
references.citation: J Chemother. 2013 Feb;25(1):26-31
references.pmid: 23433441
references.citation: J Biomol NMR. 2001 Dec;21(4):349-59
references.pmid: 11824754
references.citation: J Med Chem. 1992 Jun 12;35(12):2145-54
references.pmid: 1613742
references.citation: J Bacteriol. 2003 Jul;185(14):4136-43
references.pmid: 12837788
references.citation: Proc Natl Acad Sci U S A. 2011 Sep 13;108(37):15378-83
references.pmid: 21876172
references.citation: Acta Crystallogr D Biol Crystallogr. 2007 Dec;63(Pt 12):1208-16
references.pmid: 18084068
references.citation: Curr Protoc Bioinformatics. 2007 Jun;Chapter 8:Unit 8.12
references.pmid: 18428795
references.citation: Antimicrob Agents Chemother. 2012 Nov;56(11):5865-74
references.pmid: 22948878
references.citation: Annu Rev Biochem. 2005;74:791-831
references.pmid: 15952903
references.citation: J Biol Chem. 2013 Dec 20;288(51):36261-71
references.pmid: 24189061
references.citation: Biochemistry. 2006 Aug 22;45(33):10008-19
references.pmid: 16906759
references.citation: J Chem Inf Model. 2008 Dec;48(12):2294-307
references.pmid: 18998666
references.citation: Acc Chem Res. 2008 Jan;41(1):11-20
references.pmid: 18193820
references.citation: J Med Chem. 2006 Jan 12;49(1):159-71
references.pmid: 16392800
references.citation: J Biol Chem. 2001 Mar 2;276(9):6551-9
references.pmid: 11050088
references.citation: Drug Discov Today. 2006 Feb;11(3-4):175-80
references.pmid: 16533716