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


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.