Geraniol against multi-drug resistant bacteria – GIRC

Antibiotic resistance is an increasing problem in human health. During the last two decades, only a few molecules where proposed by the Major Companies, and with some exception (inhibition of bacterial peptide deformylase) they target the same process in bacterial cells. Indeed, there is an urgent need for new research in this field in order to isolate original hits against known and new targets. The antibiotic resistance by efflux transport is a mechanism shared by a large majority of bacteria, including the most dangerous human pathogens and the nosocomial multidrug resistant (MDR) bacteria. Addressing the inhibition of efflux, will contribute to develop suitable tools for the understanding of this ubiquitous mechanism and also will afford new compounds to further build new antibiotics.
However this aim requires a strong expertise of bacterial efflux mechanisms, and powerful methodology allowing the discrimination of interesting hits. We recently identified the geraniol as an active compound in natural essential oil that is able to restore antibiotic susceptibility of MDR isolates from Enterobacter, Acinetobacter and Pseudomonas species. It is now necessary to optimize the activity of this compound, by studying geraniol derivative molecules that may present a strongest activity and by determining this activity with various pathogens showing different MDR phenotypes and with various usual antibiotics.
The constant use of antibiotics in the hospital environment has selected bacterial populations that are resistant to many antibiotics. In particular, Enterobacter aerogenes, a commensal Gram-negative bacterium of human intestinal flora, has been rapidly emerging as an important nosocomial pathogen (Arpin et al., 1996; Davin-Regli et al., 1996; Bornet et al., 2000; De Gheldre et al., 2001) with an increasing frequency of isolates resistant to many antibiotics and antiseptics (Bosi et al., 1999). This multi-drug resistance (MDR) can result from the alteration of non-specific porins which reduce the permeability of the cell envelope to antibiotics (Charrel et al., 1996) as well as from increased active efflux of antibiotics prior to reaching their effective cytoplasmic targets (Malléa et al., 1998).
The major efflux mechanism of E. aerogenes is the AcrAB-TolC tripartite pump (Pradel and Pagès, 2002). This pump belongs to the resistance-nodulation-division family (RND), spans the inner and outer membranes of the cell envelope and actively extrudes unrelated antibiotics from the periplasm to the environement. In addition, other less characterized efflux mechanisms contribute to the MDR phenotype of E. aerogenes clinical isolates (Pradel and Pagès 2002; Chollet et al. 2004). Among the major strategies to overcome MDR bacterial resistance is the use of agents that inhibit an MDR efflux pump and therefore render the bacterium susceptible to antibiotics to which it was initially resistant (Lomovskaya and Botsian, 2006; Mahamoud et al., 2006). Although to date no EPI has yet been made available for the therapy of MDR bacterial infections, some are in pre-clinical development (Pagès et al., 2005).