Use of Efflux Pump Inhibitors (EPIs) to overcome bacterial Multi-Drug Resistance (MDR): plants as a source of chemodiversity and their adaptive response toward bacterial stress

Bacterial MDR has become a serious and general public health problem threatening both hospital and community populations and there is a strong need to provide new therapeutic solutions. Active efflux of antibiotics mediated by secondary transporters is the main mechanism responsible for the acquisition of the MDR phenotype in bacteria, rending them resistant to many structurally unrelated drugs. Bacteria that become less sensitive to treatment (by an increase in MIC) may develop more specific resistance mechanisms that lead to high-level resistant strains which cannot be treated by conventional antibiotic therapy [1]. One of the strategies employed to overcome bacterial MDR is the use of EPIs in combination with drugs which are efflux substrates, in order to restore their bactericidal activity in resistant strains. This approach is promising as it may improve the efficacy and/or extend the clinical utility of existing antibiotics [2]. Plants use antimicrobials to protect themselves from environmental stress, but their activities are often weak. With the increase and the rapid spread of resistance determinants conferring MDR phenotype in the environment, plants have to adapt their response to survive. Some authors postulate that plants use an anti-MDR strategy to potentiate their antimicrobials [3]. Based on literature and on our experimentals dealing with the isolation of EPIs from Mirabilis jalapa (Nyctaginaceae), and associated pharmacomodulation that led to compounds with significant efflux modulation activities [4], we believe that plants could be regarded as „experimental factories“ providing chemical adaptive responses toward bacterial stress, and that this function might be further enhanced with their prolonged exposure to MDR phytopathogenic bacteria.

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2. Lynch, A. S. (2006) Biochem. Pharmacol. 71: 949–956.

3. Stermitz, F. R., et al. (2000). Proc. Nat. Acad. Sci. U.S.A. 97: 1433–1437.

4. Michalet, S. et al. (2007) Bioorg. Med. Chem. Lett. 17: 1755–1758.