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Antimicrobial-resistant bacterial infections are a major and costly public health concern. Several pathogens are already pan-resistant, representing a major cause of mortality in patients suffering from nosocomial infections. Drug efflux pumps, which remove compounds from the bacterial cell, thereby lowering the antimicrobial concentration to sub-toxic levels, play a major role in multidrug resistance. In this Special Issue, we present up-to-date knowledge of the mechanism of RND efflux pumps, the identification and characterization of efflux pumps from emerging pathogens and their role in antimicrobial resistance, and progress made on the development of specific inhibitors. This collection of data could serve as a basis for antimicrobial drug discovery aimed at inhibiting drug efflux pumps to reverse resistance in some of the most resistant pathogens.

MdtF (YhiV) --- multidrug resistance --- RND-type efflux pump --- dye accumulation --- real-time efflux --- pathogens --- RND --- evolution --- efflux pump --- adaptation --- Aliarcobacter butzleri --- RND efflux pumps --- virulence --- resistance --- RND pump --- dominant negative effect --- assembly --- protein-protein interaction --- mutation --- drug resistance --- cystic fibrosis --- prevalence of efflux resistance mechanisms --- hospital acquired infections --- antibiotic resistance --- allostery --- antimicrobial resistance --- conformational changes --- energetic transition --- gram-negative bacteria --- pump activation --- n/a

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This eBook is a collection of articles from a Frontiers Research Topic. Frontiers Research Topics are very popular trademarks of the Frontiers Journals Series: they are collections of at least ten articles, all centered on a particular subject. With their unique mix of varied contributions from Original Research to Review Articles, Frontiers Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area! Find out more on how to host your own Frontiers Research Topic or contribute to one as an author by contacting the Frontiers Editorial Office: frontiersin.org/about/contact

nanomaterials --- Nanoparticles --- plant based compounds --- Antimicrobial agents --- antimicrobial resistance --- pathogens --- drug --- Alternative --- Herbal --- efflux pumps --- Tuberculosis

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The discovery of antibiotics represented a key milestone in the history of medicine. However, with the rise of these life-saving drugs came the awareness that bacteria deploy defence mechanisms to resist these antibiotics, and they are good at it. Today, we appear at a crossroads between discovery of new potent drugs and omni-resistant superbugs. Moreover, the misuse of antibiotics in different industries has increased the rate of resistance development by providing permanent selective pressure and, subsequently, enrichment of multidrug resistant pathogens. As a result, antimicrobial resistance has now become an urgent threat to public health worldwide (http://www.who.int/drugresistance/documents/surveillancereport/en/). The development of multidrug resistance (MDR) in an increasing number of pathogens, including Pseudomonas, Acinetobacter, Klebsiella, Salmonella, Burkholderia, and other Gram-negative bacteria is a most severe issue. Membrane efflux pump complexes of the Resistance-Nodulation-cell Division (RND) superfamily play a key role in the development of MDR in these bacteria. RND pumps, together with other transporters, contribute to intrinsic and acquired resistance to most, if not all, of the antimicrobial compounds available in our drug arsenal. Given the enormous drug polyspecificity of MDR efflux pumps, studies on their mechanism of action are extremely challenging, and this has negatively impacted both the development of new antibiotics that are able to evade these efflux pumps as well as the design of pump inhibitors. The collection of articles in this eBook, published as a Research Topic in Frontiers in Microbiology, section of Antimicrobials, Resistance, and Chemotherapy, aims to update the reader about the latest advances on the structure and function of RND efflux transporters, their roles in the overall multidrug resistance phenotype of Gram-negative pathogens, and on strategies to inhibit their activities. A deeper understanding of the mechanisms by which RND efflux pumps, alone or synergistically with other efflux pumps, are able to limit the concentration of antimicrobial compounds inside the bacterial cell, may pave the way for new, more directed, inhibitor and antibiotic design to ultimately overcome antimicrobial resistance by Gram-negatives.

Resistance-Nodulation Division transporters --- multi-drug-resistant pathogens --- antibiotic resistance --- Gram-Negative Bacteria --- bacterial resistance mechanisms --- Superbugs --- efflux pumps

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The brain functions within an internal environment that is determined and controlled by morphological structures and cellular mechanisms present at interfaces between the brain and the rest of the body. In vertebrates these interfaces are across cerebral blood vessels (blood-brain barrier) choroid plexuses (blood-cerebrospinal fluid barrier) and pia-arachnoid. There is a CSF-brain barrier in the neuroepithelium lining the ventricular system that is only present in embryos. There is now substantial evidence that many brain barrier mechanisms develop early and that in some cases they are functionally more active and even more specialized compared to adult barriers. Therefore barriers in developing brain should be viewed as adapted appropriately for the growing brain and not, as is still widely believed, immature. Considerable advances in our understanding of these barrier mechanisms have come from studies of the developing brain and invertebrates. A striking aspect, to be highlighted in this special edition, is that many of the molecular mechanisms in these very diverse species are similar despite differences in the cellular composition of the interfaces. This Frontiers Topic comprises articles in three sections: Original studies, Reviews and Myths & Misconceptions. Original articles provide new information on molecular and cellular barrier mechanisms in developing brains of primates, including human embryos (Brøchner et al., Ek et al., Errede et al.), rodents (Bauer et al., Liddelow, Strazielle & Ghersi-Egea, Saunders et al., Whish et al.), chick (Bueno et al.) and zebrafish (Henson et al.) as well as studies in drosophila (Hindle & Bainton, De Salvo et al., Limmer et al.). The Reviews section includes evolutionary perspectives of the blood-brain and blood-CSF barriers (Bueno et al., Bill & Korzh). There are also detailed reviews of the current state of understanding of different interfaces and their functional mechanisms in developing brain (Bauer et al., Strazielle & Gjersi-Egea, Liddelow, Richardson et al., Errede et al., Henson et al., Brøchner et al.) and in invertebrates (Hindle & Bainton, De Salvo et al., Limmer et al). Different aspects of the relationship between properties of the internal environment of the brain and its development are discussed. (Stolp & Molnar, Johansson, Prasongchean et al.). A neglected area, namely barriers over the surface of the brain during development is also covered (Brøchner et al.). Clinically related perspectives on barrier disruption in neonatal stroke are provided by Kratzer et al. and other aspects of dysfunction by Morretti et al. and by Palmeta et al. on the continuing problem of bilirubin toxicity. Progress in this field is hampered by many prevailing myths about barrier function, combined with methodologies that are not always appropriately selected or interpreted. These are covered in the Misconceptions, Myths and Methods section, including historical aspects and discussion of the paracellular pathway, a central dogma of epithelial and endothelial biology (Saunders et al.) and a review of markers used to define brain barrier integrity in development and in pathological conditions (Saunders et al.). Use of inappropriate markers has caused considerable confusion and unreliable interpretation in many published studies. Torbett et al. deal with the complexities of the new field of applying proteomics to understanding blood-brain barrier properties as do Huntley at al. with respect to applying modern high throughput gene expression methods (Huntley et al.). The Editorial summarizes the contributions from all authors. This includes mention of some the main unanswered but answerable questions in the field and what the impediments to progress may be.

zebra fish --- development --- Influx mechanisms --- Tight Junctions --- Drosophila --- Efflux mechanisms --- blood-CSF barrier --- Choroid Plexus --- Blood-Brain Barrier

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The brain functions within an internal environment that is determined and controlled by morphological structures and cellular mechanisms present at interfaces between the brain and the rest of the body. In vertebrates these interfaces are across cerebral blood vessels (blood-brain barrier) choroid plexuses (blood-cerebrospinal fluid barrier) and pia-arachnoid. There is a CSF-brain barrier in the neuroepithelium lining the ventricular system that is only present in embryos. There is now substantial evidence that many brain barrier mechanisms develop early and that in some cases they are functionally more active and even more specialized compared to adult barriers. Therefore barriers in developing brain should be viewed as adapted appropriately for the growing brain and not, as is still widely believed, immature. Considerable advances in our understanding of these barrier mechanisms have come from studies of the developing brain and invertebrates. A striking aspect, to be highlighted in this special edition, is that many of the molecular mechanisms in these very diverse species are similar despite differences in the cellular composition of the interfaces. This Frontiers Topic comprises articles in three sections: Original studies, Reviews and Myths & Misconceptions. Original articles provide new information on molecular and cellular barrier mechanisms in developing brains of primates, including human embryos (Brøchner et al., Ek et al., Errede et al.), rodents (Bauer et al., Liddelow, Strazielle & Ghersi-Egea, Saunders et al., Whish et al.), chick (Bueno et al.) and zebrafish (Henson et al.) as well as studies in drosophila (Hindle & Bainton, De Salvo et al., Limmer et al.). The Reviews section includes evolutionary perspectives of the blood-brain and blood-CSF barriers (Bueno et al., Bill & Korzh). There are also detailed reviews of the current state of understanding of different interfaces and their functional mechanisms in developing brain (Bauer et al., Strazielle & Gjersi-Egea, Liddelow, Richardson et al., Errede et al., Henson et al., Brøchner et al.) and in invertebrates (Hindle & Bainton, De Salvo et al., Limmer et al). Different aspects of the relationship between properties of the internal environment of the brain and its development are discussed. (Stolp & Molnar, Johansson, Prasongchean et al.). A neglected area, namely barriers over the surface of the brain during development is also covered (Brøchner et al.). Clinically related perspectives on barrier disruption in neonatal stroke are provided by Kratzer et al. and other aspects of dysfunction by Morretti et al. and by Palmeta et al. on the continuing problem of bilirubin toxicity. Progress in this field is hampered by many prevailing myths about barrier function, combined with methodologies that are not always appropriately selected or interpreted. These are covered in the Misconceptions, Myths and Methods section, including historical aspects and discussion of the paracellular pathway, a central dogma of epithelial and endothelial biology (Saunders et al.) and a review of markers used to define brain barrier integrity in development and in pathological conditions (Saunders et al.). Use of inappropriate markers has caused considerable confusion and unreliable interpretation in many published studies. Torbett et al. deal with the complexities of the new field of applying proteomics to understanding blood-brain barrier properties as do Huntley at al. with respect to applying modern high throughput gene expression methods (Huntley et al.). The Editorial summarizes the contributions from all authors. This includes mention of some the main unanswered but answerable questions in the field and what the impediments to progress may be.

zebra fish --- development --- Influx mechanisms --- Tight Junctions --- Drosophila --- Efflux mechanisms --- blood-CSF barrier --- Choroid Plexus --- Blood-Brain Barrier