مؤتمر
Mercapto-phosphonate compounds as broad-spectrum inhibitors of the metallo-beta-lactamases
| العنوان: | Mercapto-phosphonate compounds as broad-spectrum inhibitors of the metallo-beta-lactamases |
|---|---|
| المؤلفون: | Lassaux, Patricia, Hamel, Mathieu, Gulea, Michaela, Mercuri, Paola, Horsfall, Louise, Bebrone, Carine, Gaumont, A.-C., Frère, Jean-Marie, Galleni, Moreno |
| المصدر: | International Journal of Antimicrobial Agents, 29 (Supplément 2), S95 (2007); 17th European Congress of Clinical Microbiology and Infectious Diseases/25th International Congress of Chemotherapy, Munich, Germany [DE], 31 mars au 3 avril 2007 |
| بيانات النشر: | Elsevier, 2007. |
| سنة النشر: | 2007 |
| مصطلحات موضوعية: | Life sciences, Biochemistry, biophysics & molecular biology, Sciences du vivant, Biochimie, biophysique & biologie moléculaire |
| الوصف: | Objectives: One of the emergent factors for the b-lactam antibioticresistance of pathogenic bacteria is the production of metallob-lactamases (MBLs), which are able to hydrolyse the b-lactam ringin a broad spectrum of substrates, particularly the carbapenems. MBLshave been divided into three different sub-classes B1, B2 and B3 basedon sequence similarities [1]. In this report, we investigated the inhibitoryeffect of mercapto-phosphonate derivatives against MBLs.Methods: The laboratory of P Metzner (University of Caen, France)synthesized 12 different mercapto-phosphonate compounds with theability to inhibit the subclass B1 VIM-4, the subclass B2 CphA andthe subclass B3 L1 MBLs respectively. Consequently, we determinedthe competitive inhibition constant (Ki) as described by DeMesteret 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 mercaptophosphonatecompounds.Results: In the present study, we show that all the mercaptophosphonates,with the exception of compound 1a, behaved asgood competitive inhibitors (Ki<15 mM) for CphA. Their activitiesagainst the sub-classes B1 and B3 enzymes were more contrasted.In addition, the presence of free Zn++ abolished the inhibitoryactivity of compound 2b. The compound behaving as zinc chelatorcould explain this phenomenon. Nevertheless, the (2-sulfanylphenyl)phosphonic acid, the (4-bromophenyl)(sulfanyl)methyl phosphonic acidand the [(2,4-dichlorophenyl)(sulfanyl)methyl] phosphonic acid weregood inhibitors (Ki<15 mM) against the different studied enzymes andcan be used as leads to the synthesis of new MBL inhibitors. Our testsindicated that the presence of compounds 2b, 4a and mgfg decreasedthe MIC value for imipenem.Conclusion: In this study, we show that members of the phosphonatesgroup are able to enhance the inhibition of Zn b-lactamases. This isthe first report of new inhibitors possessing a strong activity against thedifferent sub-classes of MBLs. Reference(s)[1] Galleni M, Lamotte-Brasseur J, Rossolini GM, Spencer J, DidebergO, Frere JM. Antimicrob Agents Chemother 2001; 45(3): 660−3.[2] De Meester F, Joris B, Reckinger G, Bellefroid-Bourguignon C, FrereJM, Waley SG. Biochem Pharmacol 1987 Jul 15; 36(14): 2393–403. |
| نوع الوثيقة: | conference paper http://purl.org/coar/resource_type/c_5794 conferenceObject peer reviewed |
| اللغة: | English |
| Relation: | urn:issn:0924-8579; urn:issn:1872-7913 |
| URL الوصول: | https://orbi.uliege.be/handle/2268/302149 |
| حقوق: | open access http://purl.org/coar/access_right/c_abf2 info:eu-repo/semantics/openAccess |
| رقم الأكسشن: | edsorb.302149 |
| قاعدة البيانات: | ORBi |
| الوصف غير متاح. |