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https://www.readbyqxmd.com/read/29146106/the-hydrophobic-trap-the-achilles-heel-of-rnd-efflux-pumps
#1
Zachary Aron, Timothy J Opperman
Resistance-nodulation-division (RND) superfamily efflux pumps play a major role in multidrug resistance (MDR) of Gram-negative pathogens by extruding diverse classes of antibiotics from the cell. There has been considerable interest in developing efflux pump inhibitors (EPIs) of RND pumps as adjunctive therapies. The primary challenge in EPI discovery has been the highly hydrophobic, poly-specific substrate binding site of the target. Recent findings have identified the hydrophobic trap, a narrow phenylalanine-lined groove in the substrate-binding site, as the "Achilles heel" of the RND efflux pumps...
November 13, 2017: Research in Microbiology
https://www.readbyqxmd.com/read/29133936/the-rho-gtpase-signalling-pathway-in-urothelial-carcinoma
#2
REVIEW
Solomon L Woldu, Ryan C Hutchinson, Laura-Maria Krabbe, Oner Sanli, Vitaly Margulis
Urothelial carcinoma remains a clinical challenge: non-muscle-invasive disease has a high rate of recurrence and risk of progression, and outcomes for patients with advanced disease are poor, owing to a lack of effective systemic therapies. The Rho GTPase family of enzymes was first identified >30 years ago and contains >20 members, which are divided into eight subfamilies: Cdc42, Rac, Rho, RhoUV, RhoBTB, RhoDF, RhoH, and Rnd. Rho GTPases are molecular on-off switches, which are increasingly being understood to have a critical role in a number of cellular processes, including cell migration, cell polarity, cell adhesion, cell cycle progression, and regulation of the cytoskeleton...
November 14, 2017: Nature Reviews. Urology
https://www.readbyqxmd.com/read/29128951/insights-from-the-genomes-of-microbes-thriving-in-uranium-enriched-sediments
#3
Brodie Sutcliffe, Anthony A Chariton, Andrew J Harford, Grant C Hose, Sarah Stephenson, Paul Greenfield, David J Midgley, Ian T Paulsen
Elevated uranium dose (4 g kg(-1)) causes a shift in billabong sediment communities that result in the enrichment of five bacterial species. These taxa include Geobacter, Geothrix and Dyella species, as well as a novel-potentially predatory-Bacteroidetes species, and a new member of class Anaerolineae (Chloroflexi). Additionally, a population of methanogenic Methanocella species was also identified. Genomic reconstruction and metabolic examination of these taxa reveal a host of divergent life strategies and putative niche partitioning...
November 11, 2017: Microbial Ecology
https://www.readbyqxmd.com/read/29128373/regulation-of-the-acrab-tolc-efflux-pump-in-enterobacteriaceae
#4
Natasha Weston, Prateek Sharma, Vito Ricci, Laura J V Piddock
Bacterial multidrug efflux systems are a major mechanism of antimicrobial resistance and are fundamental to the physiology of Gram-negative bacteria. The resistance-nodulation-division (RND) family of efflux pumps is the most clinically significant, as it is associated with multidrug resistance. Expression of efflux systems is subject to multiple levels of regulation, involving local and global transcriptional regulation as well as post-transcriptional and post-translational regulation. The best-characterised RND system is AcrAB-TolC, which is present in Enterobacteriaceae...
November 8, 2017: Research in Microbiology
https://www.readbyqxmd.com/read/29118749/hoisting-loop-in-bacterial-multidrug-exporter-acrb-is-a-highly-flexible-hinge-that-enables-the-large-motion-of-the-subdomains
#5
Martijn Zwama, Katsuhiko Hayashi, Keisuke Sakurai, Ryosuke Nakashima, Kimie Kitagawa, Kunihiko Nishino, Akihito Yamaguchi
The overexpression of RND-type exporters is one of the main causes of multidrug resistance (MDR) in Gram-negative pathogens. In RND transporters, such as Escherichia coli's main efflux pump AcrB, drug efflux occurs in the porter domain, while protons flow through the transmembrane domain: remote conformational coupling. At the border of a transmembrane helix (TM8) and subdomain PC2, there is a loop which makes a hoisting movement by a random-coil-to-α-helix change, and opens and closes a drug channel entrance...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/29098252/-comparative-study-of-functional-neck-dissection-and-radical-neck-dissection-for-early-oral-squamous-cell-carcinoma
#6
Shao-Ming Li, Ling Gao, Wen-Hao Ren, Ke-Qian Zhi
PURPOSE: To evaluate the clinical effects of functional neck dissection(FND) and radical neck dissection(RND) on early oral squamous cell carcinoma (OSCC). METHODS: A total of 63 OSCC patients were divides into 2 groups. Patients in FND group (n=30) underwent functional neck dissection with preservation of sternocleidomastoid muscle, accessory nerve, internal jugular vein and great auricular nerve, while patients in RND group (n=33) underwent radical neck dissection...
June 2017: Shanghai Kou Qiang Yi Xue, Shanghai Journal of Stomatology
https://www.readbyqxmd.com/read/29050760/mmps5-mmpl5-as-an-efflux-pump-in-mycobacterium-species
#7
REVIEW
Julien Briffotaux, Wei Huang, Xinwei Wang, Brigitte Gicquel
Tuberculosis remains an important cause of morbidity and mortality throughout the world, amplified by the expansion of antibiotic resistance. Increasing active efflux of the antibiotic is one of the several strategies used by bacteria to resist to antibiotics. After showing the importance of the RND superfamily of efflux pumps in drug resistance, this review focuses on the protein MmpL5, a transmembrane transporter of Mycobacterium. These exporters should be involved in the variety of roles in bacterial cells, including expelling various drugs...
December 2017: Tuberculosis
https://www.readbyqxmd.com/read/29042652/computational-analysis-of-the-molecular-mechanism-of-ramr-mutations-contributing-to-antimicrobial-resistance-in-salmonella-enterica
#8
Yen-Yi Liu, Chih-Chieh Chen
Antimicrobial resistance (AMR) in pathogenic microorganisms with multidrug resistance (MDR) constitutes a severe threat to human health. A major causative mechanism of AMR is mediated through the multidrug efflux pump (MEP). The resistance-nodulation-division superfamily (RND family) of Gram-negative bacteria is usually the major cause of MDR in clinical studies. In Salmonella enterica, the RND pump is translated from the arcAB gene, which is regulated by the activator RamA. Many MEP-caused AMR strains have high ramA gene expression due to mutations in RamR, which has a homodimeric structure comprising the dimerization domain and DNA-binding domain (DBD)...
October 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29042503/erratum-for-hagan-et-al-petrobactin-is-exported-from-bacillus-anthracis-by-the-rnd-type-exporter-apex
#9
A K Hagan, A Tripathi, D Berger, D H Sherman, P C Hanna
No abstract text is available yet for this article.
October 17, 2017: MBio
https://www.readbyqxmd.com/read/29040270/analysis-of-the-interaction-of-plexin-b1-and-plexin-b2-with-rnd-family-proteins
#10
Thomas Wylie, Ritu Garg, Anne J Ridley, Maria R Conte
The Rnd family of proteins, Rnd1, Rnd2 and Rnd3, are atypical Rho family GTPases, which bind to but do not hydrolyse GTP. They interact with plexins, which are receptors for semaphorins, and are hypothesised to regulate plexin signalling. We recently showed that each Rnd protein has a distinct profile of interaction with three plexins, Plexin-B1, Plexin-B2 and Plexin-B3, in mammalian cells, although it is unclear which region(s) of these plexins contribute to this specificity. Here we characterise the binary interactions of the Rnd proteins with the Rho-binding domain (RBD) of Plexin-B1 and Plexin-B2 using biophysical approaches...
2017: PloS One
https://www.readbyqxmd.com/read/28951954/evolution-of-structural-fitness-and-multifunctional-aspects-of-mycobacterial-rnd-family-transporters
#11
REVIEW
Padmani Sandhu, Yusuf Akhter
Drug resistance is a major concern due to the evolution and emergence of pathogenic bacterial strains with novel strategies to resist the antibiotics in use. Mycobacterium tuberculosis (Mtb) is one of such pathogens with reported strains, which are not treatable with any of the available anti-TB drugs. This scenario has led to the need to look for some novel drug targets in Mtb, which may be exploited to design effective treatment strategies against the infection. The goal of this review is to discuss one such class of emerging drug targets in Mtb...
September 26, 2017: Archives of Microbiology
https://www.readbyqxmd.com/read/28922614/mexxy-efflux-pump-overexpression-and-aminoglycoside-resistance-in-cystic-fibrosis-isolates-of-pseudomonas-aeruginosa-from-chronic-infections
#12
Manu Singh, Yvonne C W Yau, Shirley Wang, Valerie Waters, Ayush Kumar
In this study, we analyzed 15 multidrug-resistant cystic fibrosis isolates of Pseudomonas aeruginosa from chronic lung infections for expression of 4 different multidrug efflux systems (MexAB-OprM, MexCD-OprJ, MexEF-OprN, and MexXY), using quantitative reverse transcriptase PCR. Overexpression of MexXY pump was observed in all of the isolates tested. Analysis of regulatory genes that control the expression of these 4 efflux pumps revealed a number of previously uncharacterized mutations. Our work shows that MexXY pump overexpression is common in cystic fibrosis isolates and could be contributing to their reduced aminoglycoside susceptibility...
September 18, 2017: Canadian Journal of Microbiology
https://www.readbyqxmd.com/read/28916560/cmeabc-multidrug-efflux-pump-contributes-to-antibiotic-resistance-and-promotes-campylobacter-jejuni-survival-and-multiplication-in-acanthamoeba-polyphaga
#13
Ana Vieira, Amritha Ramesh, Alan M Seddon, Andrey V Karlyshev
Campylobacter jejuni is a foodborne pathogen recognized as the leading cause of human bacterial gastroenteritis. The wide use of antibiotics in medicine and in animal husbandry has led to an increased incidence of antibiotic resistance in Campylobacter In addition to a role in multidrug resistance, the Campylobacter CmeABC RND-type efflux pump, which is associated with multidrug resistance (MDR), may also be involved in virulence. As a vehicle of pathogenic microorganisms, the protozoan Acanthamoeba is a good model for the investigation of bacterial survival in the environment and molecular mechanisms of pathogenicity...
September 15, 2017: Applied and Environmental Microbiology
https://www.readbyqxmd.com/read/28900249/effect-of-efflux-pump-inhibition-on-pseudomonas-aeruginosa-transcriptome-and-virulence
#14
Giordano Rampioni, Cejoice Ramachandran Pillai, Francesca Longo, Roslen Bondì, Valerio Baldelli, Marco Messina, Francesco Imperi, Paolo Visca, Livia Leoni
Efflux pumps of the resistance-nodulation-cell-division (RND) family increase antibiotic resistance in many bacterial pathogens, representing candidate targets for the development of antibiotic adjuvants. RND pumps have also been proposed to contribute to bacterial infection, implying that efflux pump inhibitors (EPIs) could also act as anti-virulence drugs. Nevertheless, EPIs are usually investigated only for their properties as antibiotic adjuvants, while their potential anti-virulence activity is seldom taken into account...
September 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28900020/petrobactin-is-exported-from-bacillus-anthracis-by-the-rnd-type-exporter-apex
#15
A K Hagan, A Tripathi, D Berger, D H Sherman, P C Hanna
Bacillus anthracis-a Gram-positive, spore-forming bacterium-causes anthrax, a highly lethal disease with high bacteremia titers. Such rapid growth requires ample access to nutrients, including iron. However, access to this critical metal is heavily restricted in mammals, which requires B. anthracis to employ petrobactin, an iron-scavenging small molecule known as a siderophore. Petrobactin biosynthesis is mediated by asb gene products, and import of the iron-bound (holo)-siderophore into the bacterium has been well studied...
September 12, 2017: MBio
https://www.readbyqxmd.com/read/28890187/kinetic-analysis-of-the-inhibition-of-the-drug-efflux-protein-acrb-using-surface-plasmon-resonance
#16
Rumana Mowla, Yinhu Wang, Shutao Ma, Henrietta Venter
Multidrug efflux protein complexes such as AcrAB-TolC from Escherichia coli are paramount in multidrug resistance in Gram-negative bacteria and are also implicated in other processes such as virulence and biofilm formation. Hence efflux pump inhibition, as a means to reverse antimicrobial resistance in clinically relevant pathogens, has gained increased momentum over the past two decades. Significant advances in the structural and functional analysis of AcrB have informed the selection of efflux pump inhibitors (EPIs)...
September 7, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28867620/complete-genome-sequence-analysis-of-the-fish-pathogen-flavobacterium-columnare-provides-insights-into-antibiotic-resistance-and-pathogenicity-related-genes
#17
Yulei Zhang, Lijuan Zhao, Wenjie Chen, Yunmao Huang, Ling Yang, V Sarathbabu, Zaohe Wu, Jun Li, Pin Nie, Li Lin
We analyzed here the complete genome sequences of a highly virulent Flavobacterium columnare Pf1 strain isolated in our laboratory. The complete genome consists of a 3,171,081 bp circular DNA with 2784 predicted protein-coding genes. Among these, 286 genes were predicted as antibiotic resistance genes, including 32 RND-type efflux pump related genes which were associated with the export of aminoglycosides, indicating inducible aminoglycosides resistances in F. columnare. On the other hand, 328 genes were predicted as pathogenicity related genes which could be classified as virulence factors, gliding motility proteins, adhesins, and many putative secreted proteases...
October 2017: Microbial Pathogenesis
https://www.readbyqxmd.com/read/28808284/molecular-rationale-behind-the-differential-substrate-specificity-of-bacterial-rnd-multi-drug-transporters
#18
Venkata Krishnan Ramaswamy, Attilio V Vargiu, Giuliano Malloci, Jürg Dreier, Paolo Ruggerone
Resistance-Nodulation-cell Division (RND) transporters AcrB and AcrD of Escherichia coli expel a wide range of substrates out of the cell in conjunction with AcrA and TolC, contributing to the onset of bacterial multidrug resistance. Despite sharing an overall sequence identity of ~66% (similarity ~80%), these RND transporters feature distinct substrate specificity patterns whose underlying basis remains elusive. We performed exhaustive comparative analyses of the putative substrate binding pockets considering crystal structures, homology models and conformations extracted from multi-copy μs-long molecular dynamics simulations of both AcrB and AcrD...
August 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28806947/conessine-as-a-novel-inhibitor-of-multidrug-efflux-pump-systems-in-pseudomonas-aeruginosa
#19
Thanyaluck Siriyong, Potjanee Srimanote, Sasitorn Chusri, Boon-Ek Yingyongnarongkul, Channarong Suaisom, Varomyalin Tipmanee, Supayang Piyawan Voravuthikunchai
BACKGROUND: Holarrhena antidysenterica has been employed as an ethnobotanical plant for the treatment of dysentery, diarrhoea, fever, and bacterial infections. Biological activities of the principle compound, conessine including anti-diarrhoea and anti-plasmodial effects were documented. Our previous study reported potency of Holarrhena antidysenterica extract and conessine as resistance modifying agents against extensively drug-resistant Acinetobacter baumannii. This study aimed to investigate (i) whether conessine, a steroidal alkaloid compound, could act as a resistance modifying agent against multidrug-resistant Pseudomonas aeruginosa, and (ii) whether MexAB-OprM efflux pump involved in the mechanism...
August 14, 2017: BMC Complementary and Alternative Medicine
https://www.readbyqxmd.com/read/28764143/prevalence-of-flexible-flat-foot-in-adults-a-cross-sectional-study
#20
Ashok Aenumulapalli, Manoj Mohan Kulkarni, Achleshwar Ramnarain Gandotra
INTRODUCTION: Flat foot (pes planus) is a commonly observed disorder in clinical practice. The height of Medial Longitudinal Arch (MLA) determines the degree of pes planus. Majority of the previous studies on prevalence of flexible flat foot were done among children. AIM: The present study was undertaken to determine the prevalence of flexible flat foot among 18-21-year-old Indian adults using Navicular Drop Test (NDT) which is regarded as reliable and valid method to characterise MLA...
June 2017: Journal of Clinical and Diagnostic Research: JCDR
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