Inhibitors of Bacterial Efflux Pumps as Adjuvants in Antibacterial Therapy and Diagnostic Tools for
Detection of Resistance by Efflux

In: Frontiers in Anti-Infective Drug Discovery, 2010, 1, 138-175, Atta-ur-Rahman / M. Iqbal Choudhary (Eds.)

Françoise Van Bambeke, Jean-Marie Pagès and Ving J. Lee

Unité de Pharmacologie Cellulaire et Moleculaire, Université catholique de Louvain, Brussels, Belgium;
EA2197 Enveloppe Bactérienne, Perméabilité et Antibiotiques, Faculté de Médecine, Université de la Méditerranée, Marseille, France;
Adesis, Inc., New Castle, DE 19720, USA & Limerick BioPharma, Inc., South San Francisco, CA 94080 USA


Active efflux is a wide-spread 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 analogues of antibiotic substrates [tetracyclines, quinolones or aminoglycosides] and others are
new chemical entities [including substituted indoles, ureas, aromatic amides, piperidinecarboxylic acids, alkylamino- or alkoxyquinolines, peptidomimetics, and
pyridopyrimidines]. Their spectrum of activity, in terms of companion 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.

Keywords: Efflux pumps, resistance, S. aureus, S. pneumoniae, H. influenzae, E. coli, P.aeruginosa,
E. aerogenes, reserpine, indoles, ureas, aromatic amides, piperidine-carboxylic acid derivatives, quinolines, peptidomimetics.