Design, synthesis, and biological evaluation of α-hydroxyacyl-AMS inhibitors of amino acid adenylation enzymes.
Biosynthesis of bacterial natural-product virulence factors is emerging as a promising antibiotic target. Many such natural products are produced by nonribosomal peptide synthetases (NRPS) from amino acid precursors. To develop selective inhibitors of these pathways, we have previously described aminoacyl-AMS (sulfamoyladenosine) macrocycles that inhibit NRPS amino acid adenylation domains but not mechanistically-related aminoacyl-tRNA synthetases. To improve the cell permeability of these inhibitors, we explore herein replacement of the α-amino group with an α-hydroxy group. In both macrocycles and corresponding linear congeners, this leads to decreased biochemical inhibition of the cysteine adenylation domain of the Yersina pestis siderophore synthetase HMWP2, which we attribute to loss of an electrostatic interaction with a conserved active-site aspartate. However, inhibitory activity can be regained by installing a cognate β-thiol moiety in the linear series. This provides a path forward to develop selective, cell-penetrant inhibitors of the biosynthesis of virulence factors to probe their biological functions and potential as therapeutic targets.
Pharmacology Program, Weill Cornell Graduate School of Medical Sciences, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 422, New York, NY 10065, United States.
Tony D
TD
Davis
Department of Biology, Brooklyn College, City University of New York, 2900 Bedford Avenue, Brooklyn, NY 11210, United States; Biology Program, Graduate Center, City University of New York, 365 Fifth Avenue, New York, NY 10016, United States.
Poornima
P
Mohandas
Chemical Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 422, New York, NY 10065, United States.
Maria I
MI
Chiriac
Department of Biology, Brooklyn College, City University of New York, 2900 Bedford Avenue, Brooklyn, NY 11210, United States; Biology Program, Graduate Center, City University of New York, 365 Fifth Avenue, New York, NY 10016, United States.
Glennon V
GV
Bythrow
Department of Biology, Brooklyn College, City University of New York, 2900 Bedford Avenue, Brooklyn, NY 11210, United States; Biology Program, Graduate Center, City University of New York, 365 Fifth Avenue, New York, NY 10016, United States.
Luis E N
LE
Quadri
Pharmacology Program, Weill Cornell Graduate School of Medical Sciences, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 422, New York, NY 10065, United States; Chemical Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 422, New York, NY 10065, United States; Tri-Institutional Research Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 422, New York, NY 10065, United States.
Derek S
DS
Tan
D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D000596:Amino Acids / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D010453:Peptide Synthases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D000596:Amino Acids; D004791:Enzyme Inhibitors; D010453:Peptide Synthases; C104385:non-ribosomal peptide synthase; D000241:Adenosine
Adenylation; Antibiotic; Non-ribosomal peptide synthetase; Rational design; Virulence
Biochemistry. 2007 Apr 3;46(13):4147-57
17346033
Biochemistry. 2013 Feb 5;52(5):926-37
23302043
Chem Biol. 2011 Nov 23;18(11):1432-41
22118677
J Infect Dis. 2013 Oct 15;208(8):1255-65
23788726
Nature. 2012 May 23;485(7399):439-40
22622552
Org Biomol Chem. 2006 Oct 7;4(19):3598-610
16990935
Bioorg Med Chem. 2014 Mar 1;22(5):1726-35
24507827
Metallomics. 2015 Jun;7(6):986-95
25745886
J Mol Biol. 2004 Apr 2;337(4):857-69
15033356
J Med Chem. 2006 Jan 12;49(1):31-4
16392788
Am Nat. 2007 Sep;170(3):331-42
17879185
Biochemistry. 2010 Nov 2;49(43):9292-305
20853905
J Biol Chem. 2004 Jul 23;279(30):31717-26
15145952
PLoS Pathog. 2015 Mar 27;11(3):e1004792
25815898
Nat Rev Drug Discov. 2015 Aug;14 (8):529-42
26139286
Nat Rev Drug Discov. 2010 Feb;9(2):117-28
20081869
Nat Rev Microbiol. 2004 Dec;2(12):946-53
15550940
Infect Immun. 1997 May;65(5):1659-68
9125544
Infect Immun. 2012 Mar;80(3):1015-24
22232188
EMBO J. 1999 Nov 15;18(22):6532-41
10562565
Biochim Biophys Acta. 1969;185(2):269-86
4980133
Chem Rev. 2006 Aug;106(8):3468-96
16895337
Appl Environ Microbiol. 2015 Feb;81(4):1502-12
25527542
J Med Chem. 2008 May 22;51(10):3020-9
18438987
Chembiochem. 2012 Jan 2;13(1):129-36
22109989
J Mol Biol. 1989 Jul 5;208(1):83-98
2504923
J Med Chem. 2008 May 22;51(10 ):2871-8
18260614
Biochim Biophys Acta. 1991 Oct 25;1080(2):126-34
1932086
Bioorg Med Chem Lett. 2006 Jul 15;16(14):3802-5
16678412
Chem Biol. 2008 Jan;15(1):51-61
18158259
Infect Disord Drug Targets. 2007 Sep;7(3):230-7
17897059
Chembiochem. 2003 Sep 5;4(9):903-6
12964169
Infect Immun. 1996 Jul;64(7):2834-8
8698519
Microbiology. 2002 Dec;148(Pt 12):3873-80
12480891
Infect Immun. 2008 Aug;76(8):3539-49
18541653
MBio. 2011 Oct 11;2(5):null
21990612
Chem Soc Rev. 2008 Jul;37(7):1320-9
18568158
BMC Microbiol. 2012 Jul 20;12:143
22817680
Nat Chem Biol. 2009 Mar;5(3):166-73
19182784
Methods Enzymol. 1979;63:437-67
502865
Chem Biol. 1999 Aug;6(8):493-505
10421756
PLoS One. 2015 Jun 04;10(6):e0128569
26042597
Front Microbiol. 2014 Jan 24;5:1
24478763
ACS Chem Biol. 2015 Dec 18;10 (12 ):2816-26
26474351
Infect Immun. 1994 Nov;62(11):5120-5
7927795
J Mol Biol. 1999 Apr 2;287(3):555-68
10092459
Science. 2006 Aug 11;313(5788):848-51
16902142
Curr Opin Microbiol. 2009 Apr;12(2):205-14
19251475
ACS Chem Biol. 2014 Nov 21;9(11):2535-44
25198656
FEBS J. 2006 Jan;273(2):409-19
16403027
Biochim Biophys Acta. 2015 Aug;1854(8):1054-70
25970810
Infect Immun. 1979 Apr;24(1):174-80
156695
Nature. 2016 Jan 21;529(7586):336-43
26791724
Infect Immun. 1996 Feb;64(2):518-23
8550201
Science. 2010 Jul 16;329(5989):294-6
20522739
Nat Rev Microbiol. 2006 Apr;4(4):249-58
16501584
Biochemistry. 2012 Nov 6;51(44):8705-29
23075299
Nature. 2006 Mar 16;440(7082):372-6
16541080
Microbiol Mol Biol Rev. 2013 Mar;77(1):73-111
23471618
Philos Trans R Soc Lond B Biol Sci. 2007 Jul 29;362(1483):1195-200
17360275
Org Lett. 2004 Feb 19;6(4):497-500
14961607
Nat Chem Biol. 2005 Jun;1(1):29-32
16407990
Cold Spring Harb Perspect Med. 2012 Nov 01;2(11):null
23125205
Annu Rev Microbiol. 2000;54:881-941
11018148
Structure. 1998 Apr 15;6(4):439-49
9562563
Curr Opin Struct Biol. 2009 Dec;19(6):666-71
19836944
Nat Chem Biol. 2007 Sep;3(9):541-8
17710100
Chembiochem. 2008 Nov 3;9(16):2606-11
18821554
Bioorg Med Chem Lett. 2008 Nov 15;18(22):5963-6
18762421
FEBS J. 2005 Jun;272(12):2993-3003
15955059
Mol Microbiol. 2008 Mar;67(5):971-83
18194158
Biochemistry. 2010 May 4;49(17):3648-57
20359185
Biochemistry. 2015 Oct 27;54(42):6514-24
26394156
J Bacteriol. 2014 Apr;196(7):1343-9
24443535
J Am Chem Soc. 2007 Jun 27;129(25):7752-3
17542590
Nat Rev Microbiol. 2014 Apr;12 (4):300-8
24625893
EMBO J. 1997 Jul 16;16(14):4174-83
9250661
Biochemistry. 2000 Jul 25;39(29):8418-25
10913247
Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12120-5
12221282
Curr Top Med Chem. 2012;12(7):766-96
22283817
Infect Immun. 2000 Apr;68(4):1834-9
10722571
Antimicrob Agents Chemother. 2013 Oct;57(10):5138-40
23856770
Anal Biochem. 2010 Sep 1;404(1):56-63
20450872
Biochemistry. 2008 Nov 25;47(47):12434-47
18973344
Org Biomol Chem. 2010 Dec 21;8(24):5486-9
20852771
Appl Microbiol Biotechnol. 2003 May;61(4):278-88
12743756