In recent times we are getting used to the daunting news about the spreading of “bad bugs”, bacteria escaping the action of all known antibiotics. These multi-drug resistant (MDR) bacteria are well documented, particularly within nosocomial settings and include Gram-negative pathogens Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, and Neisseria gonorrhoeae.
In these MDR pathogens a major contribution to intrinsic and acquired resistance comes from the changes in the outer and inner membrane composition, i.e. from the alterations in the structure of outer membrane lipopolysaccharides, the reduced expression of outer membrane porins, and the upregulation of efflux pumps. These combined mechanisms drastically reduce permeation of antibiotics and bactericides into the periplasm and the cytoplasm, thus reducing the effective concentration of the drug to the target sites in these compartments. Furthermore, they gives bacteria the opportunity to reinforce more specific mechanisms such as enzymatic inactivation and modification of the drug target(s).
While porins are passive diffusion channels for antibiotics, MDR efflux pumps are ATP or pmf-driven exporters with enormous drug polyspecificity. In addition, they have been recognized as virulence factors and are involved in biofilm formation. Among the various families of efflux pumps, the Resistance-Nodulation-cell-Division (RND) one is the most prevalent in MDR Gram-negative bacteria, and is the only family whose representatives span the entire cell envelope, expelling noxious chemicals directly out of the cell. It has been recently demonstrated how RND pumps are involved in a coordinated network of different transporters with overlapping specificities, providing the bacteria with a robust survival strategy against antibacterials.
It is thus not surprising how designing new antibiotics able to escape efflux is a formidable task not yet achieved by the scientific community or by the pharmaceutical companies. A promising approach is the so-called combination therapy, where an efflux pump inhibitor (EPI) is co-administrated in order to to enhance the activity of an antibiotic. Despite the therapeutic potential of efflux pump inhibition, the research in this field (as well in the alternative approaches) is still in its infancy, and in order to inform studies that attempt to circumvent resistance by efflux pumps, we urgently need a greater understanding of the biological, genetic, structural and molecular determinants of MDR.
This call aims at collecting the latest advances in our knowledge of resistance mediated by the RND family of efflux pumps, from their genomics to the molecular mechanism of drug recognition and transport and finally to the possible inhibition strategies. While the focus is mainly on efflux pumps of the RND family, studies or reviews concerned with other families are welcomed, particularly if they focus on the interplay among different pumps in order to get a more general picture of the full efflux-mediated resistance.
In recent times we are getting used to the daunting news about the spreading of “bad bugs”, bacteria escaping the action of all known antibiotics. These multi-drug resistant (MDR) bacteria are well documented, particularly within nosocomial settings and include Gram-negative pathogens Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, and Neisseria gonorrhoeae.
In these MDR pathogens a major contribution to intrinsic and acquired resistance comes from the changes in the outer and inner membrane composition, i.e. from the alterations in the structure of outer membrane lipopolysaccharides, the reduced expression of outer membrane porins, and the upregulation of efflux pumps. These combined mechanisms drastically reduce permeation of antibiotics and bactericides into the periplasm and the cytoplasm, thus reducing the effective concentration of the drug to the target sites in these compartments. Furthermore, they gives bacteria the opportunity to reinforce more specific mechanisms such as enzymatic inactivation and modification of the drug target(s).
While porins are passive diffusion channels for antibiotics, MDR efflux pumps are ATP or pmf-driven exporters with enormous drug polyspecificity. In addition, they have been recognized as virulence factors and are involved in biofilm formation. Among the various families of efflux pumps, the Resistance-Nodulation-cell-Division (RND) one is the most prevalent in MDR Gram-negative bacteria, and is the only family whose representatives span the entire cell envelope, expelling noxious chemicals directly out of the cell. It has been recently demonstrated how RND pumps are involved in a coordinated network of different transporters with overlapping specificities, providing the bacteria with a robust survival strategy against antibacterials.
It is thus not surprising how designing new antibiotics able to escape efflux is a formidable task not yet achieved by the scientific community or by the pharmaceutical companies. A promising approach is the so-called combination therapy, where an efflux pump inhibitor (EPI) is co-administrated in order to to enhance the activity of an antibiotic. Despite the therapeutic potential of efflux pump inhibition, the research in this field (as well in the alternative approaches) is still in its infancy, and in order to inform studies that attempt to circumvent resistance by efflux pumps, we urgently need a greater understanding of the biological, genetic, structural and molecular determinants of MDR.
This call aims at collecting the latest advances in our knowledge of resistance mediated by the RND family of efflux pumps, from their genomics to the molecular mechanism of drug recognition and transport and finally to the possible inhibition strategies. While the focus is mainly on efflux pumps of the RND family, studies or reviews concerned with other families are welcomed, particularly if they focus on the interplay among different pumps in order to get a more general picture of the full efflux-mediated resistance.
