title: Discovery of inhibitors of Escherichia coli methionine aminopeptidase with the Fe(II)-form selectivity and antibacterial activity.
abstract: Methionine aminopeptidase (MetAP) is a promising target to develop novel antibiotics, because all bacteria express MetAP from a single gene that carries out the essential function of removing N-terminal methionine from nascent proteins. Divalent metal ions play a critical role in the catalysis, and there is an urgent need to define the actual metal used by MetAP in bacterial cells. By high throughput screening, we identified a novel class of catechol-containing MetAP inhibitors that display selectivity for the Fe(II)-form of MetAP. X-ray structure revealed that the inhibitor binds to MetAP at the active site with the catechol coordinating to the metal ions. Importantly, some of the inhibitors showed antibacterial activity at low micromolar concentration on Gram-positive and Gram-negative bacteria. Our data indicate that Fe(II) is the likely metal used by MetAP in the cellular environment, and MetAP inhibitors need to inhibit this metalloform of MetAP effectively to be therapeutically useful.
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
authors.forename: Wen-Long
authors.initials: WL
authors.lastname: Wang
authors.forename: Sergio C
authors.initials: SC
authors.lastname: Chai
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.forename: Hong-Zhen
authors.initials: HZ
authors.lastname: He
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Hurley
authors.forename: Qi-Zhuang
authors.initials: QZ
authors.lastname: Ye
mesh_terms: D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects* / Q000201:enzymology* / Q000254:growth & development; D007501:Iron / Q000737:chemistry; D063208:Methionyl Aminopeptidases; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D054852:Small Molecule Libraries; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D007501:Iron; D000626:Aminopeptidases; D063208:Methionyl Aminopeptidases
references.citation: Trends Biochem Sci. 1998 Jul;23(7):263-7
references.pmid: 9697417
references.citation: Biochem Biophys Res Commun. 2003 Jul 18;307(1):172-9
references.pmid: 12849997
references.citation: J Bacteriol. 1989 Jul;171(7):4071-2
references.pmid: 2544569
references.citation: J Med Chem. 2003 Jun 19;46(13):2631-40
references.pmid: 12801227
references.citation: Biochemistry. 1999 Aug 24;38(34):11079-85
references.pmid: 10460163
references.citation: Biochim Biophys Acta. 2000 Mar 7;1477(1-2):157-67
references.pmid: 10708856
references.citation: J Biomol Screen. 1999;4(2):67-73
references.pmid: 10838414
references.citation: Acta Crystallogr D Biol Crystallogr. 1994 Sep 1;50(Pt 5):760-3
references.pmid: 15299374
references.citation: Acta Crystallogr D Biol Crystallogr. 1997 May 1;53(Pt 3):240-55
references.pmid: 15299926
references.citation: J Bacteriol. 1989 Sep;171(9):5215-7
references.pmid: 2670909
references.citation: Biochemistry. 2003 May 6;42(17):5035-42
references.pmid: 12718546
references.citation: J Am Chem Soc. 2005 Feb 23;127(7):2317-23
references.pmid: 15713111
references.citation: J Org Chem. 2004 Apr 2;69(7):2362-6
references.pmid: 15049631
references.citation: Protein Sci. 1998 Dec;7(12):2684-7
references.pmid: 9865965
references.citation: Angew Chem Int Ed Engl. 2005 Jun 6;44(23):3620-3
references.pmid: 15880695
references.citation: J Med Chem. 2004 Mar 11;47(6):1325-8
references.pmid: 14998322
references.citation: Bioorg Med Chem Lett. 2005 Dec 15;15(24):5386-91
references.pmid: 16219464
references.citation: FEMS Microbiol Lett. 1989 Oct 1;52(1-2):23-6
references.pmid: 2689280
references.citation: Microbiol Mol Biol Rev. 2002 Jun;66(2):223-49
references.pmid: 12040125
references.citation: J Bacteriol. 1969 Mar;97(3):1334-42
references.pmid: 4887513
references.citation: Biochemistry. 2002 Oct 29;41(43):13096-105
references.pmid: 12390038
references.citation: Acta Crystallogr D Biol Crystallogr. 2003 Jul;59(Pt 7):1131-7
references.pmid: 12832755
references.citation: Curr Med Chem. 2002 Feb;9(3):385-409
references.pmid: 11860363
references.citation: Acta Crystallogr D Biol Crystallogr. 2001 Oct;57(Pt 10):1373-82
references.pmid: 11567148
references.citation: Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2126-32
references.pmid: 15572765
references.citation: Acta Crystallogr D Biol Crystallogr. 2006 Apr;62(Pt 4):425-32
references.pmid: 16552144
references.citation: Biochemistry. 2001 Sep 4;40(35):10645-54
references.pmid: 11524009
references.citation: Inorg Chem. 2001 Jun 18;40(13):3181-90
references.pmid: 11399191
references.citation: J Am Chem Soc. 2004 Nov 3;126(43):13940-1
references.pmid: 15506752
references.citation: Bioorg Med Chem Lett. 2005 Feb 1;15(3):639-44
references.pmid: 15664829