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Mercapto-phosphonate compounds as broad-spectrum inhibitors of the metallo-beta-lactamases
Lassaux, Patricia; Hamel, Mathieu; Gulea, Michaela et al.
2007In International Journal of Antimicrobial Agents, 29 (Supplément 2), p. 95
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Abstract :
[en] Objectives: One of the emergent factors for the b-lactam antibiotic resistance of pathogenic bacteria is the production of metallob- lactamases (MBLs), which are able to hydrolyse the b-lactam ring in a broad spectrum of substrates, particularly the carbapenems. MBLs have been divided into three different sub-classes B1, B2 and B3 based on sequence similarities [1]. In this report, we investigated the inhibitory effect of mercapto-phosphonate derivatives against MBLs. Methods: The laboratory of P Metzner (University of Caen, France) synthesized 12 different mercapto-phosphonate compounds with the ability to inhibit the subclass B1 VIM-4, the subclass B2 CphA and the subclass B3 L1 MBLs respectively. Consequently, we determined the competitive inhibition constant (Ki) as described by DeMester et al. [2]. We also measured the minimal inhibition concentration (MIC) for Escherichia coli recombinant strains producing VIM-4, CphA or L1, for ampicillin or imipenem in the presence or absence of mercaptophosphonate compounds. Results: In the present study, we show that all the mercaptophosphonates, with the exception of compound 1a, behaved as good competitive inhibitors (Ki<15 mM) for CphA. Their activities against the sub-classes B1 and B3 enzymes were more contrasted. In addition, the presence of free Zn++ abolished the inhibitory activity of compound 2b. The compound behaving as zinc chelator could explain this phenomenon. Nevertheless, the (2-sulfanylphenyl) phosphonic acid, the (4-bromophenyl)(sulfanyl)methyl phosphonic acid and the [(2,4-dichlorophenyl)(sulfanyl)methyl] phosphonic acid were good inhibitors (Ki<15 mM) against the different studied enzymes and can be used as leads to the synthesis of new MBL inhibitors. Our tests indicated that the presence of compounds 2b, 4a and mgfg decreased the MIC value for imipenem. Conclusion: In this study, we show that members of the phosphonates group are able to enhance the inhibition of Zn b-lactamases. This is the first report of new inhibitors possessing a strong activity against the different sub-classes of MBLs. Reference(s) [1] Galleni M, Lamotte-Brasseur J, Rossolini GM, Spencer J, Dideberg O, Frere JM. Antimicrob Agents Chemother 2001; 45(3): 660−3. [2] De Meester F, Joris B, Reckinger G, Bellefroid-Bourguignon C, Frere JM, Waley SG. Biochem Pharmacol 1987 Jul 15; 36(14): 2393–403.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Lassaux, Patricia ;  Université de Liège - ULiège > Centres généraux > Centre d'ingénierie des protéines
Hamel, Mathieu;  UCBN - Université de Caen Basse-Normandie [FR]
Gulea, Michaela;  UCBN - Université de Caen Basse-Normandie [FR]
Mercuri, Paola ;  Université de Liège - ULiège > Département des sciences de la vie > Macromolécules biologiques
Horsfall, Louise ;  Université de Liège - ULiège > Centres généraux > Centre d'ingénierie des protéines
Bebrone, Carine ;  Université de Liège - ULiège > Centres généraux > Centre d'ingénierie des protéines
Gaumont, A.-C.;  UCBN - Université de Caen Basse-Normandie [FR]
Frère, Jean-Marie ;  Université de Liège - ULiège > Département des sciences de la vie > Centre d'Ingénierie des Protéines (CIP)
Galleni, Moreno ;  Université de Liège - ULiège > Département des sciences de la vie > Macromolécules biologiques
Language :
English
Title :
Mercapto-phosphonate compounds as broad-spectrum inhibitors of the metallo-beta-lactamases
Publication date :
2007
Event name :
17th European Congress of Clinical Microbiology and Infectious Diseases/25th International Congress of Chemotherapy
Event place :
Munich, Germany
Event date :
31 mars au 3 avril 2007
Event number :
O453
Audience :
International
Journal title :
International Journal of Antimicrobial Agents
ISSN :
0924-8579
eISSN :
1872-7913
Publisher :
Elsevier, Amsterdam, Netherlands
Volume :
29
Issue :
Supplément 2
Pages :
S95
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 30 April 2023

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