Convergent biosynthetic pathways to β-lactam antibiotics.
Five naturally-occurring families of β-lactams have inspired a class of drugs that constitute >60% of the antimicrobials used in human medicine. Their biosynthetic pathways reveal highly individualized synthetic strategies that yet converge on a common azetidinone ring assembled in structural contexts that confer selective binding and inhibition of d,d-transpeptidases that play essential roles in bacterial cell wall (peptidoglycan) biosynthesis. These enzymes belong to a single 'clan' of evolutionarily distinct serine hydrolases whose active site geometry and mechanism of action is specifically matched by these antibiotics for inactivation that is kinetically competitive with their native function. Unusual enzyme-mediated reactions and catalytic multitasking in these pathways are discussed with particular attention to the diverse ways the β-lactam itself is generated, and more broadly how the intrinsic reactivity of this core structural element is modulated in natural systems through the introduction of ring strain and electronic effects.
Department of Chemistry, Johns Hopkins University, 3400 N. Charles Street, Baltimore, MD 21218, USA. Electronic address: ctownsend@jhu.edu.
Craig A
CA
Townsend
D000900:Anti-Bacterial Agents / Q000096:biosynthesis*; D002384:Catalysis; D006801:Humans; D007700:Kinetics; D047090:beta-Lactams / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D047090:beta-Lactams
Biochemistry. 2010 Nov 23;49(46):9946-7
20964365
Chembiochem. 2014 Jan 24;15(2):320-31
24420617
Proc Natl Acad Sci U S A. 2013 Feb 19;110(8):E653-61
23382230
Chem Biol. 2012 Feb 24;19(2):297-306
22365611
Nat Struct Biol. 2001 Aug;8(8):684-9
11473258
Chembiochem. 2011 Sep 19;12(14):2159-65
21913298
Nucleic Acids Res. 2016 Jan 4;44(D1):D343-50
26527717
Chem Biol. 2004 Jul;11(7):927-38
15271351
J Am Chem Soc. 2013 Feb 6;135(5):1749-59
23330869
Methods Enzymol. 2009;458:337-51
19374989
J Med Chem. 1996 Jun 7;39(12):2367-78
8691431
Nature. 2015 Apr 16;520(7547):383-7
25624104
J Biol Chem. 2004 Feb 20;279(8):6730-6
14625287
Nat Chem Biol. 2014 Nov;10(11):963-8
25262415
J Biol Chem. 1998 Nov 13;273(46):30695-703
9804844
Cell Chem Biol. 2016 Mar 17;23 (3):331-9
26991102
Chem Biol. 1999 Aug;6(8):493-505
10421756
Chembiochem. 2004 Jun 7;5(6):879-82
15174175
Proc Natl Acad Sci U S A. 2002 Nov 12;99(23):14752-7
12409610
J Mol Biol. 2002 Oct 25;323(3):585-98
12381311
Arch Biochem Biophys. 2003 May 1;413(1):23-31
12706338
Biochemistry. 2010 Oct 19;49(41):8815-7
20845982
Antimicrob Agents Chemother. 2013 Dec;57(12):5940-5
24041897
Nat Chem Biol. 2014 Apr;10(4):251-8
24531841
Nature. 2016 Jan 21;529(7586):336-43
26791724
J Am Chem Soc. 2003 Jul 16;125(28):8486-93
12848554
J Am Chem Soc. 2007 Dec 26;129(51):15750-1
18052280
J Am Chem Soc. 2003 Dec 24;125(51):15746-7
14677956
Chem Rev. 2005 Feb;105(2):715-38
15700962
Nat Prod Rep. 2013 Jan;30(1):21-107
23135477
Proc Natl Acad Sci U S A. 2015 Aug 18;112(33):10354-8
26240322
Chem Rev. 1997 Nov 10;97(7):2631-2650
11851475
Org Lett. 2014 May 2;16(9):2454-7
24730694
Biochemistry. 2003 Jul 1;42(25):7836-47
12820893
Biochemistry. 2004 Dec 21;43(50):15936-45
15595850
Chem Biol. 2000 Mar;7(3):211-24
10712928
J Bacteriol. 2008 Jun;190(12):4360-6
18408028
Science. 2014 Mar 7;343(6175):1140-4
24604200
Proc Natl Acad Sci U S A. 2008 Aug 12;105(32):11128-33
18678912
Biochemistry. 2009 Jun 9;48(22):4959-71
19371088
J Biol Chem. 2004 Feb 13;279(7):5685-92
14623876
J Org Chem. 2013 Jul 5;78(13):6412-26
23758494
Antimicrob Agents Chemother. 1982 Apr;21(4):558-64
6805424
Chembiochem. 2002 Jun 3;3(6):490-504
12325005
Chem Biol. 2003 Apr;10(4):301-11
12725858
Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9082-6
9689037