[en] The development of broad-spectrum metallo-beta-lactamase (MBL) inhibitors is challenging due to structural diversity and differences in metal utilisation by these enzymes. Analysis of structural data, followed by non-denturing mass spectrometric analyses, identified thiols proposed to inhibit representative MBLs from all three sub-classes: B1, B2 and B3. Solution analyses led to the identification of broad spectrum inhibitors, including potent inhibitors of the CphA MBL (Aeromonas hydrophila). Structural studies revealed that, as observed for other B1 and B3 MBLs, inhibition of the L1 MBL thiols involves metal chelation. Evidence is reported that this is not the case for inhibition of the CphA enzyme by some thiols; the crystal structure of the CphA-Zn-inhibitor complex reveals a binding mode in which the thiol does not interact with the zinc. The structural data enabled the design and the production of further more potent inhibitors. Overall the results suggest that the development of reasonably broad-spectrum MBL inhibitors should be possible.
Disciplines :
Chemistry
Author, co-author :
Lienard, Benoit M R
Garau, Gianpiero
Horsfall, Louise
Karsisiotis, Andreas I
Damblon, Christian ; Université de Liège - ULiège > Département de chimie (sciences) > Chimie biologique structurale
Lassaux, Patricia ; Université de Liège - ULiège > Centre d'ingénierie des protéines
Papamicael, Cyril
Roberts, Gordon C K
Galleni, Moreno ; Université de Liège - ULiège > Département des sciences de la vie > Macromolécules biologiques
Dideberg, Otto
Frère, Jean-Marie ; Université de Liège - ULiège > Centre d'ingénierie des protéines
Schofield, Christopher J
Language :
English
Title :
Structural basis for the broad-spectrum inhibition of metallo-beta-lactamases by thiols
Publication date :
2008
Journal title :
Organic and Biomolecular Chemistry
ISSN :
1477-0520
eISSN :
1477-0539
Publisher :
Royal Society of Chemistry, Cambridge, United Kingdom
T. R. Walsh M. A. Toleman L. Poirel P. Nordmann Clin. Microbiol. Rev. 2005 18 306 325
A. Felici G. Amicosante A. Oratore R. Strom P. Ledent B. Joris L. Fanuel J. M. Frere Biochem. J. 1993 291 151 155
B. Segatore O. Massidda G. Satta D. Setacci G. Amicosante Antimicrob. Agents Chemother. 1993 37 1324 1328
M. Hernandez Valladares A. Felici G. Weber H. W. Adolph M. Zeppezauer G. M. Rossolini G. Amicosante J. M. Frere M. Galleni Biochemistry 1997 36 11534 11541
G. Garau C. Bebrone C. Anne M. Galleni J. M. Frere O. Dideberg J. Mol. Biol. 2005 345 785 795
C. Damblon C. Prosperi L. Y. Lian I. Barsukov R. P. Soto M. Galleni J. M. Frere G. C. K. Roberts J. Am. Chem. Soc. 1999 121 11575 11576
C. Damblon M. Jensen A. Ababou I. Barsukov C. Papamicael C. J. Schofield L. Olsen R. Bauer G. C. Roberts J. Biol. Chem. 2003 278 29240 29251
N. O. Concha C. A. Janson P. Rowling S. Pearson C. A. Cheever B. P. Clarke C. Lewis M. Galleni J. M. Frere D. J. Payne J. H. Bateson S. S. Abdel-Meguid Biochemistry 2000 39 4288 4298
J. H. Toney G. G. Hammond P. M. Fitzgerald N. Sharma J. M. Balkovec G. P. Rouen S. H. Olson M. L. Hammond M. L. Greenlee Y. D. Gao J. Biol. Chem. 2001 276 31913 31918
C. Mollard C. Moali C. Papamicael C. Damblon S. Vessilier G. Amicosante C. J. Schofield M. Galleni J. M. Frere G. C. Roberts J. Biol. Chem. 2001 276 45015 45023
U. Heinz R. Bauer S. Wommer W. Meyer-Klaucke C. Papamichaels J. Bateson H. W. Adolph J. Biol. Chem. 2003 278 20659 20666
J. D. Buynak H. Chen L. Vogeti V. R. Gadhachanda C. A. Buchanan T. Palzkill R. W. Shaw J. Spencer T. R. Walsh Bioorg. Med. Chem. Lett. 2004 14 1299 1304
Q. Sun A. Law M. W. Crowder H. M. Geysen Bioorg. Med. Chem. Lett. 2006 16 5169 5175
N. Selevsek A. Tholey E. Heinzle B. M. Lienard N. J. Oldham C. J. Schofield U. Heinz H. W. Adolph J. M. Frere J. Am. Soc. Mass Spectrom. 2006 17 1000 1004
A. Carfi E. Duee M. Galleni J. M. Frere O. Dideberg Acta Crystallogr., Sect. D: Biol. Crystallogr. 1998 54 313 323
J. H. Ullah T. R. Walsh I. A. Taylor D. C. Emery C. S. Verma S. J. Gamblin J. Spencer J. Mol. Biol. 1998 284 125 136
I. Garcia-Saez P. S. Mercuri C. Papamicael R. Kahn J. M. Frere M. Galleni G. M. Rossolini O. Dideberg J. Mol. Biol. 2003 325 651 660
J. Gao X. Cheng R. Chen G. B. Sigal J. E. Bruce B. L. Schwartz S. A. Hofstadler G. A. Anderson R. D. Smith G. M. Whitesides J. Med. Chem. 1996 39 1949 1955
J. L. Benesch C. V. Robinson Curr. Opin. Struct. Biol. 2006 16 245 251
A. J. Heck R. H. Van Den Heuvel Mass Spectrom. Rev. 2004 23 368 389
J. A. Loo Mass Spectrom. Rev. 1997 16 1 23
H. A. Staab R. G. H. Kirrstetter Liebigs Ann. Chem. 1979 6 886 898
M. A. Ondetti and D. W. Cushman, Ger. Pat. DE 2717548, 1977
H. K. Chenault J. Dahmer G. M. Whitesides J. Am. Chem. Soc. 1989 111 6354 6364
S. Bounaga M. Galleni A. P. Laws M. I. Page Bioorg. Med. Chem. 2001 9 503 510
R. A. Williamson M. D. Carr T. A. Frenkiel J. Feeney R. B. Freedman Biochemistry 1997 36 13882 13889
I. Garcia-Saez J. Hopkins C. Papamicael N. Franceschini G. Amicosante G. M. Rossolini M. Galleni J. M. Frere O. Dideberg J. Biol. Chem. 2003 278 23868 23873
R. Natesh S. L. U. Schwager H. R. Evans E. D. Sturrock K. R. Acharya Biochemistry 2004 43 8718 8724
R. Natesh S. L. U. Schwager E. D. Sturrock K. R. Acharya Nature 2003 421 551 554
