Medicinal Plants Classification Biosynthesis and ... - Index of

Medicinal Plants: A Tool to Overcome Antibiotic Resistance?
4.1. Efflux Pumps Inhibitors
4.1.1. Efflux Systems
Among the major mechanisms involved in bacterial resistance, efflux pumps, responsible
for the extrusion of the antibiotic outside the cell, have recently received a particular
attention. These systems can confer resistance to a specific class of antibiotics or to a large
number of drugs, thus conferring a multi-drug resistance to bacteria. Efflux pumps are
currently classified into five families:
� ATP-binding cassette (ABC) transporters are ubiquitous membrane systems involved
in different transport functions such as the efflux of toxins, metabolites and drugs.
Bacterial ABC transporters involved in drug resistance are mainly drug-specific
transporters and many of them are found in antibiotic producing organisms, such as
Streptomyces spp, thus ensuring self-resistance to the drug they produce. In some
Gram positive bacteria, such as Staphylococci and Enterococci, such specific
transporters are also found, conferring resistance to macrolides and related
compounds (Holland, 2003).
� Major facilitator superfamily (MFS) are ubiquitous systems ensuring transport of
sugars, intermediate metabolites and drugs.
� Resistance nodulation and cell division (RDN) are involved in the transport of
lipophilic and amphiphilic molecules or toxic divalent cations, also responsible for
the solvent resistance of some bacterial strains. They are mainly found in Gram
negative bacteria.
� Small multi-drugs resistance (SMR) are the smallest drug efflux proteins known,
involved in the efflux of lipophilic cationic drugs.
� Multi-drug and toxic compounds extrusion (MATE) are mainly Na + /drug antiporters
in contrast to the other families of secondary transporters which act as proton/drug
antiporters.
These five families of efflux pumps are commonly grouped in two major groups based
upon bioenergetical and structural features: (i) the primary transporters which hydrolyze ATP
as source of energy (ABC transporters); and (ii) the secondary transporters which use the
proton (or sodium) gradient as source of energy (MFS, RDN, SMR and MATE). In bacteria,
secondary transporters are dominant and many of them are multi-drugs resistance
transporters, whereas ABC transporters are mainly specific drug resistance transporters.
In Gram positive bacteria, MDR is mainly conferred by MFS efflux systems, the most
studied being NorA of Staphylococcus aureus and its homologues in Bacillus subtilis, Mmr
and Blt. Whereas RDN efflux systems are major contributors to resistance for Gram negative
bacteria, AcrAB-TolC and MexAB-OprM are also involved in the intrinsic resistance of
Escherichia coli and Pseudomonas aeruginosa, respectively.
4.1.2. Efflux Pumps Inhibitors (EPIs)
The research of compounds inhibiting the efflux pumps is crucial in the fight against
antibiotic resistance. These compounds are expected to: (i) decrease the intrinsic resistance of
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