Reference : Current challenges in antimicrobial chemotherapy: focus on beta-lactamase inhibition.
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
http://hdl.handle.net/2268/3887
Current challenges in antimicrobial chemotherapy: focus on beta-lactamase inhibition.
English
Bebrone, Carine mailto [Université de Liège - ULg > > Centre d'ingénierie des protéines >]
Lassaux, Patricia mailto [Université de Liège - ULg > > Centre d'ingénierie des protéines >]
Vercheval, Lionel [Université de Liège - ULg > > Centre d'ingénierie des protéines >]
Sohier, Jean mailto [Université de Liège - ULg > Département des sciences de la vie > Macromolécules biologiques >]
Jehaes, Adrien mailto [Université de Liège - ULg > > > Doct. sc. (bioch., bioch. mol.&cell., bioinf.&mod.-Bologne)]
Sauvage, Eric mailto [Université de Liège - ULg > > Centre d'ingénierie des protéines >]
Galleni, Moreno mailto [Université de Liège - ULg > Département des sciences de la vie > Macromolécules biologiques >]
16-Apr-2010
Drugs
Adis Press
70(6)
651-679
Yes (verified by ORBi)
International
0012-6667
Auckland
New Zealand
[en] The use of the three classical beta-lactamase inhibitors (clavulanic acid, tazobactam, sulbactam) in combination with beta-lactam antibiotics is currently the most successful strategy to combat the beta-lactamase mediated resistance. However, these inhibitors are efficient in inactivating class A beta-lactamases only and the efficiency of the inhibitor/antibiotic combination can be compromised by several mechanisms among which the production of naturally resistant class B or class D enzymes, the hyperproduction of AmpC or even the production of evolved inhibitor-resistant class A enzymes. There is thus an urgent need in the development of novel inhibitors. For serine active enzymes (classes A, C and D), derivatives of the beta-lactam ring such as 6-beta-halogenopenicillanates, beta-lactam sulfones, penems and oxapenems, monobactams or trinems seem to be potential starting points to design efficient molecules (among which AM-112 and LK-157). Moreover, a promising non-beta-lactam molecule, NXL-104 is now under clinical trial. In contrast, an ideal inhibitor of metallo-beta-lactamases (class B) remains to be found, despite the huge number of potential molecules already described (biphenyl tetrazoles, cysteinyl peptides, mercaptocarboxylates, succinic acid derivatives, etc). The search for such an inhibitor is complicated by the absence of a covalent intermediate in their catalytic mechanisms and the fact that beta-lactam derivatives often behave as substrates rather than as inhibitors. Currently, the most promising broad spectrum inhibitors of class B enzymes are molecules presenting chelating groups (thiols, carboxylates, etc) combined with an aromatic group.
This review describes all the types of molecules already tested as potential beta-lactamase inhibitors and thus constitutes an update of the current status in beta-lactamase inhibitor discovery.
Centre d'Ingénierie des Protéines - CIP
Fonds de la Recherche Scientifique (Communauté française de Belgique) - F.R.S.-FNRS
http://hdl.handle.net/2268/3887
http://adisonline.com/drugs/pages/articleviewer.aspx?year=2010&issue=70060&article=00002&type=abstract

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