Editorial [Hot topic: Control and Regulation of Permeability of MDR Bacterial Pathogens to Antibiotics Presented by COST Action BM0701 (Guest Editors: L. Amaral and J.M. Pages)]

Multi-drug resistance of Gram-negative and Gram-positive bacteria is essentially due to functional changes of the cell envelope which reduce the over-permeability of the bacterium to antibiotics and in some cases, to biocides. The major components of the Gram-negative cell envelope that control the permeability of the bacterium to noxious agents (antibiotics, antimicrobials, biocides and other toxins) are: i) the lipopolysaccharide cover of the outer cell membrane whose effectiveness can be increased by a two component regulatory system when the bacterium is exposed to noxious compounds; ii) a reduction in the number of channels (porins) that allow lipophobic to traverse the outer cell envelope and reach internal compartments of the cell when the bacterium is exposed to noxious compounds; and iii) over-expressed efflux pumps that recognize noxious agents that reach the periplasm or cytoplasm of the bacterium and extrude these compounds prior to their reaching their intended targets. The response of the Gram negative bacterium to noxious compounds may involve all of these components. The manner by which the bacterium organizes the individual response of each of these regulators of permeability is highly relevant to clinical medicine since these responses render the organism increasingly resistant to two or more unrelated antibiotics, and often times to entire families of antibiotics. Moreover, it is now clear that regardless of how recent a new and effective antibiotic is introduced for the therapy of Gram-negative bacterial infections, the response of the global bacterial population as a consequence of increased usage of the antibiotic, soon renders the organisms multi-drug resistant. Understanding the mechanisms by which bacteria trigger the development of multi-drug resistance requires the concerted efforts of many widely diverse areas of science and technology. From clinical bacteriology, molecular and structural biology, biochemistry and bacterial physiology, molecular modeling and chemical synthesis, much knowledge must be achieved regarding the regulation of membrane permeability, the structure, the membrane topology and the activity of the involved drug transporters. The main objective of the COST1 Action ATENS (BM0701) is to organize a framework of collaboration between well-known experts in these scientific areas necessary for understanding membrane-mediated resistance at the molecular and genetic levels and to translate this knowledge into the development of diagnostic tests and antimicrobials that will, in the future, help control MDR infectious diseases. This program links the research disciplines of biology, physical-chemistry and medicine through pools of teams belonging to several European countries and different chapters of this issue have been written by these partners. This multi- and inter- disciplinary aspect will be a prominent advantage of ATENS that will yield major weapons to be used against our favourite enemy, the microbe. This issue of the Current Drug Targets contains articles written by European scientists that are leaders in the field of efflux mediated multi-drug resistance of clinically important bacteria. The articles discuss the structural biology of the efflux pumps of Gram negative bacteria, the control of permeability by the joint action of efflux pumps and the outer membrane channels of Gram negative bacteria, the regulation of efflux pumps by regulator genes, the relevance of efflux pump mediated mdr of bacteria, the development of molecular models that measure on a real-time basis the movement of antibiotic molecules through a porin channel, the development of methods that identify efflux mediated mdr bacteria, and the potential therapy of efflux mediated mdr infections by agents that have been used for decades for non-infectious pathology. Each of the articles provides a substantial listing of references that by itself, yields the information that will readily result in the acquired expertise in what was once a most difficult to understand area of infectious disease-namely, the control and regulation of permeability of mdr bacteria to antibiotics. We hope the readers will enjoy this issue and direct their students to the contents of this special issue of “Current Drug Targets”.