Recent Patents on Anti-Infective Drug Discovery, 2006, 1, 157-175 157
Inhibitors of Bacterial Efflux Pumps as Adjuvants in Antibiotic Treatments and
Diagnostic Tools for Detection of Resistance by Efflux
Françoise Van Bambeke1,*, Jean-Marie Pagès2 and Ving J. Lee3
1Unité de Pharmacologie cellulaire et moléculaire, Université
catholique de Louvain, Brussels, Belgium 2EA2197
Enveloppe Bactérienne, Perméabilité et Antibiotiques, Faculté
de Médecine, Université de la Méditerranée, Marseille,
France; 3CB Research and Development, Inc. (Adesis, Inc), New Castle, DE, USA
Abstract:
Active efflux is a widespread mechanism for bacterial resistance to antibiotics,
which contributes to poor
intrinsic susceptibility, cross-resistance to structurally diverse classes of
drugs, or selection of other mechanisms of
resistance. Thus, inhibition of efflux pumps appears to be (i) a promising strategy
for restoring the activity of existing
antibiotics, and (ii) a useful method to detect the presence of efflux determinants
in clinical isolates. Structurally
dissimilar classes of inhibitors have been patented in the last decade, some
are analogs of antibiotic substrates
[tetracyclines, quinolones or aminoglycosides] and others, new chemical entities
[including substituted indoles, ureas,
aromatic amides, piperidinecarboxylic acids, alkylamino- or alkoxyquinolines,
peptidomimetics, and pyridopyrimidines].
Their spectrum of activity, in terms of antibiotics and bacteria, differ significantly.
Narrow spectrum inhibitors are of
prime interest as diagnostic tools, while broad spectrum inhibitors are expected
for adjuvant therapies. Apart from (i) a
peptidomimetic inhibitor of Mex pumps in Pseudomonas aeruginosa (MC-04,124),
for which efficacy was evaluated in
animal models, and (ii) a piperidinecarboxylic acid inhibitor of fluoroquinolone
efflux in Gram-positive (VX-710), which
was safely administered to humans, most of these products have only demonstrated
their activity in vitro, so further
investigations are needed to evaluate their clinical potential.