Article (Scientific journals)
Current challenges in antimicrobial chemotherapy: focus on beta-lactamase inhibition.
Bebrone, Carine; Lassaux, Patricia; Vercheval, Lionel et al.
2010In Drugs, 70(6), p. 651-679
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Abstract :
[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.
Research center :
CIP - Centre d'Ingénierie des Protéines - ULiège
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Bebrone, Carine ;  Université de Liège - ULiège > Centre d'ingénierie des protéines
Lassaux, Patricia ;  Université de Liège - ULiège > Centre d'ingénierie des protéines
Vercheval, Lionel ;  Université de Liège - ULiège > Centre d'ingénierie des protéines
Sohier, Jean ;  Université de Liège - ULiège > Département des sciences de la vie > Macromolécules biologiques
Jehaes, Adrien ;  Université de Liège - ULiège > Doct. sc. (bioch., bioch. mol.&cell., bioinf.&mod.-Bologne)
Sauvage, Eric ;  Université de Liège - ULiège > Centre d'ingénierie des protéines
Galleni, Moreno ;  Université de Liège - ULiège > Département des sciences de la vie > Macromolécules biologiques
Language :
English
Title :
Current challenges in antimicrobial chemotherapy: focus on beta-lactamase inhibition.
Publication date :
16 April 2010
Journal title :
Drugs
ISSN :
0012-6667
eISSN :
1179-1950
Publisher :
Adis Press, Auckland, New Zealand
Volume :
70(6)
Pages :
651-679
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE]
Available on ORBi :
since 29 April 2010

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