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
Abstract:
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.