The Experts below are selected from a list of 369 Experts worldwide ranked by ideXlab platform
Martin F. Desimone - One of the best experts on this subject based on the ideXlab platform.
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silica core shell particles for the dual delivery of gentamicin and Rifamycin Antibiotics
Journal of Materials Chemistry B, 2016Co-Authors: Andrea M. Mebert, Carole Aimé, Gisela S. Alvarez, Yupeng Shi, Silvia E. Lucangioli, Martin F. Desimone, Sabrina FlorAbstract:Increasing bacterial resistance calls for the simultaneous delivery of multiple Antibiotics. One strategy is to design a unique pharmaceutical carrier that is able to incorporate several drugs with different physico-chemical properties. This is highly challenging as it may require the development of compartmentalization approaches. Here we have prepared core–shell silica particles allowing for the dual delivery of gentamicin and Rifamycin. The effect of silica particle surface functionalization on antibiotic sorption was first studied, enlightening the role of electrostatic and hydrophobic interactions. This in turn dictates the chemical conditions for shell deposition and further sorption of these Antibiotics. In particular, the silica shell deposition was favored by the positively charged layer of gentamicin coating on the core particle surface. Shell modification by thiol groups finally allowed for Rifamycin sorption. The antibacterial activity of the core–shell particles against Staphylococcus aureus and Pseudomonas aeruginosa demonstrated the dual release and action of the two Antibiotics.
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Silica core–shell particles for the dual delivery of gentamicin and Rifamycin Antibiotics
Journal of materials chemistry B, 2016Co-Authors: Andrea M. Mebert, Carole Aimé, Gisela S. Alvarez, Yupeng Shi, Sabrina A. Flor, Silvia E. Lucangioli, Martin F. Desimone, Thibaud CoradinAbstract:Increasing bacterial resistance calls for the simultaneous delivery of multiple Antibiotics. One strategy is to design a unique pharmaceutical carrier that is able to incorporate several drugs with different physico-chemical properties. This is highly challenging as it may require the development of compartmentalization approaches. Here we have prepared core–shell silica particles allowing for the dual delivery of gentamicin and Rifamycin. The effect of silica particle surface functionalization on antibiotic sorption was first studied, enlightening the role of electrostatic and hydrophobic interactions. This in turn dictates the chemical conditions for shell deposition and further sorption of these Antibiotics. In particular, the silica shell deposition was favored by the positively charged layer of gentamicin coating on the core particle surface. Shell modification by thiol groups finally allowed for Rifamycin sorption. The antibacterial activity of the core–shell particles against Staphylococcus aureus and Pseudomonas aeruginosa demonstrated the dual release and action of the two Antibiotics.
Gerard D Wright - One of the best experts on this subject based on the ideXlab platform.
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Rox, a Rifamycin Resistance Enzyme with an Unprecedented Mechanism of Action.
Cell Chemical Biology, 2018Co-Authors: Kalinka Koteva, Linda Ejim, Georgina Cox, Jayne K. Kelso, Matthew D. Surette, Haley L. Zubyk, Peter J. Stogios, Alexei Savchenko, Dan Sørensen, Gerard D WrightAbstract:Rifamycin monooxygenases (Rox) are present in a variety of environmental bacteria and are associated with decomposition of the clinically utilized antibiotic rifampin. Here we report the structure and function of a drug-inducible rox gene from Streptomyces venezuelae, which encodes a class A flavoprotein monooxygenase that inactivates a broad range of Rifamycin Antibiotics. Our findings describe a mechanism of Rifamycin inactivation initiated by monooxygenation of the 2-position of the naphthyl group, which subsequently results in ring opening and linearization of the antibiotic. The result is an antibiotic that no longer adopts the basket-like structure essential for binding to the RNA exit tunnel of the target RpoB, thereby providing the molecular logic of resistance. This unique mechanism of enzymatic inactivation underpins the broad spectrum of Rifamycin resistance mediated by Rox enzymes and presents a new antibiotic resistance mechanism not yet seen in microbial antibiotic detoxification.
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a Rifamycin inactivating phosphotransferase family shared by environmental and pathogenic bacteria
Proceedings of the National Academy of Sciences of the United States of America, 2014Co-Authors: Peter Spanogiannopoulos, Kalinka Koteva, Nicholas Waglechner, Gerard D WrightAbstract:Many environmental bacteria are multidrug-resistant and represent a reservoir of ancient antibiotic resistance determinants, which have been linked to genes found in pathogens. Exploring the environmental antibiotic resistome, therefore, reveals the diversity and evolution of antibiotic resistance and also provides insight into the vulnerability of clinically used Antibiotics. In this study, we describe the identification of a highly conserved regulatory motif, the rifampin (RIF) -associated element (RAE), which is found upstream of genes encoding RIF-inactivating enzymes from a diverse collection of actinomycetes. Using gene expression assays, we confirmed that the RAE is involved in RIF-responsive regulation. By using the RAE as a probe for new RIF-associated genes in several actinomycete genomes, we identified a heretofore unknown RIF resistance gene, RIF phosphotransferase (rph). The RPH enzyme is a RIF-inactivating phosphotransferase and represents a new protein family in antibiotic resistance. RPH orthologs are widespread and found in RIF-sensitive bacteria, including Bacillus cereus and the pathogen Listeria monocytogenes. Heterologous expression and in vitro enzyme assays with purified RPHs from diverse bacterial genera show that these enzymes are capable of conferring high-level resistance to a variety of clinically used Rifamycin Antibiotics. This work identifies a new antibiotic resistance protein family and reinforces the fact that the study of resistance in environmental organisms can serve to identify resistance elements with relevance to pathogens.
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Characterization of a Rifampin-Inactivating Glycosyltransferase from a Screen of Environmental Actinomycetes
Antimicrobial agents and chemotherapy, 2012Co-Authors: Peter Spanogiannopoulos, Kalinka Koteva, Nicholas Waglechner, Maulik N. Thaker, Gerard D WrightAbstract:Identifying and understanding the collection of all antibiotic resistance determinants presented in the global microbiota, the antibiotic resistome, provides insight into the evolution of antibiotic resistance and critical information for the development of future antimicrobials. The Rifamycins are broad-spectrum Antibiotics that target bacterial transcription by inhibition of RNA polymerase. Although mutational alteration of the drug target is the predominant mechanism of resistance to this family of Antibiotics in the clinic, a number of diverse inactivation mechanisms have also been reported. In this report, we investigate a subset of environmental rifampin-resistant actinomycete isolates and identify a diverse collection of rifampin inactivation mechanisms. We describe a single isolate, WAC1438, capable of inactivating rifampin by glycosylation. A draft genome sequence of WAC1438 (most closely related to Streptomyces speibonae, according to a 16S rRNA gene comparison) was assembled, and the associated rifampin glycosyltransferase open reading frame, rgt1438, was identified. The role of rgt1438 in rifampin resistance was confirmed by its disruption in the bacterial chromosome, resulting in a loss of antibiotic inactivation and a 4-fold decrease in MIC. Interestingly, examination of the RNA polymerase β-subunit sequence of WAC1438 suggests that it harbors a resistant target and thus possesses dual mechanisms of Rifamycin resistance. Using an in vitro assay with purified enzyme, Rgt1438 could inactivate a variety of Rifamycin Antibiotics with comparable steady-state kinetics constants. Our results identify rgt1438 as a rifampin resistance determinant from WAC1438 capable of inactivating an assortment of Rifamycins, adding a new element to the rifampin resistome.
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Rifamycin antibiotic resistance by adp ribosylation structure and diversity of arr
Proceedings of the National Academy of Sciences of the United States of America, 2008Co-Authors: Jennifer Baysarowich, Kalinka Koteva, Donald W Hughes, Linda Ejim, Emma Griffiths, Kun Zhang, Murray S Junop, Gerard D WrightAbstract:The Rifamycin antibiotic rifampin is important for the treatment of tuberculosis and infections caused by multidrug-resistant Staphylococcus aureus. Recent iterations of the rifampin core structure have resulted in new drugs and drug candidates for the treatment of a much broader range of infectious diseases. This expanded use of Rifamycin Antibiotics has the potential to select for increased resistance. One poorly characterized mechanism of resistance is through Arr enzymes that catalyze ADP-ribosylation of Rifamycins. We find that genes encoding predicted Arr enzymes are widely distributed in the genomes of pathogenic and nonpathogenic bacteria. Biochemical analysis of three representative Arr enzymes from environmental and pathogenic bacterial sources shows that these have equally efficient drug resistance capacity in vitro and in vivo. The 3D structure of one of these orthologues from Mycobacterium smegmatis was determined and reveals structural homology with ADP-ribosyltransferases important in eukaryotic biology, including poly(ADP-ribose) polymerases (PARPs) and bacterial toxins, despite no significant amino acid sequence homology with these proteins. This work highlights the extent of the Rifamycin resistome in microbial genera with the potential to negatively impact the expanded use of this class of antibiotic.
Andrea M. Mebert - One of the best experts on this subject based on the ideXlab platform.
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silica core shell particles for the dual delivery of gentamicin and Rifamycin Antibiotics
Journal of Materials Chemistry B, 2016Co-Authors: Andrea M. Mebert, Carole Aimé, Gisela S. Alvarez, Yupeng Shi, Silvia E. Lucangioli, Martin F. Desimone, Sabrina FlorAbstract:Increasing bacterial resistance calls for the simultaneous delivery of multiple Antibiotics. One strategy is to design a unique pharmaceutical carrier that is able to incorporate several drugs with different physico-chemical properties. This is highly challenging as it may require the development of compartmentalization approaches. Here we have prepared core–shell silica particles allowing for the dual delivery of gentamicin and Rifamycin. The effect of silica particle surface functionalization on antibiotic sorption was first studied, enlightening the role of electrostatic and hydrophobic interactions. This in turn dictates the chemical conditions for shell deposition and further sorption of these Antibiotics. In particular, the silica shell deposition was favored by the positively charged layer of gentamicin coating on the core particle surface. Shell modification by thiol groups finally allowed for Rifamycin sorption. The antibacterial activity of the core–shell particles against Staphylococcus aureus and Pseudomonas aeruginosa demonstrated the dual release and action of the two Antibiotics.
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Silica core–shell particles for the dual delivery of gentamicin and Rifamycin Antibiotics
Journal of materials chemistry B, 2016Co-Authors: Andrea M. Mebert, Carole Aimé, Gisela S. Alvarez, Yupeng Shi, Sabrina A. Flor, Silvia E. Lucangioli, Martin F. Desimone, Thibaud CoradinAbstract:Increasing bacterial resistance calls for the simultaneous delivery of multiple Antibiotics. One strategy is to design a unique pharmaceutical carrier that is able to incorporate several drugs with different physico-chemical properties. This is highly challenging as it may require the development of compartmentalization approaches. Here we have prepared core–shell silica particles allowing for the dual delivery of gentamicin and Rifamycin. The effect of silica particle surface functionalization on antibiotic sorption was first studied, enlightening the role of electrostatic and hydrophobic interactions. This in turn dictates the chemical conditions for shell deposition and further sorption of these Antibiotics. In particular, the silica shell deposition was favored by the positively charged layer of gentamicin coating on the core particle surface. Shell modification by thiol groups finally allowed for Rifamycin sorption. The antibacterial activity of the core–shell particles against Staphylococcus aureus and Pseudomonas aeruginosa demonstrated the dual release and action of the two Antibiotics.
Thulasi Warrier - One of the best experts on this subject based on the ideXlab platform.
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Rifamycin congeners kanglemycins are active against rifampicin resistant bacteria via a distinct mechanism
Nature Communications, 2018Co-Authors: James Peek, Mirjana Lilic, Daniel Montiel, Aleksandr Milshteyn, Ian Woodworth, John B. Biggins, Melinda A. Ternei, Paula Y. Calle, Michael Danziger, Thulasi WarrierAbstract:Rifamycin Antibiotics (Rifs) target bacterial RNA polymerases (RNAPs) and are widely used to treat infections including tuberculosis. The utility of these compounds is threatened by the increasing incidence of resistance (RifR). As resistance mechanisms found in clinical settings may also occur in natural environments, here we postulated that bacteria could have evolved to produce Rifamycin congeners active against clinically relevant resistance phenotypes. We survey soil metagenomes and identify a tailoring enzyme-rich family of gene clusters encoding biosynthesis of Rifamycin congeners (kanglemycins, Kangs) with potent in vivo and in vitro activity against the most common clinically relevant RifR mutations. Our structural and mechanistic analyses reveal the basis for Kang inhibition of RifR RNAP. Unlike Rifs, Kangs function through a mechanism that includes interfering with 5′-initiating substrate binding. Our results suggest that examining soil microbiomes for new analogues of clinically used Antibiotics may uncover metabolites capable of circumventing clinically important resistance mechanisms.
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Rifamycin congeners kanglemycins are active against rifampicin-resistant bacteria via a distinct mechanism
Nature Publishing Group, 2018Co-Authors: James Peek, Mirjana Lilic, Daniel Montiel, Aleksandr Milshteyn, Ian Woodworth, John B. Biggins, Melinda A. Ternei, Paula Y. Calle, Michael Danziger, Thulasi WarrierAbstract:Resistance to Rifamycin Antibiotics, which target bacterial RNA polymerases, is a growing problem. Here, the authors identify gene clusters from soil metagenomes encoding production of Rifamycin analogues that are active against rifampicin-resistant bacteria through a distinct mechanism
Gisela S. Alvarez - One of the best experts on this subject based on the ideXlab platform.
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silica core shell particles for the dual delivery of gentamicin and Rifamycin Antibiotics
Journal of Materials Chemistry B, 2016Co-Authors: Andrea M. Mebert, Carole Aimé, Gisela S. Alvarez, Yupeng Shi, Silvia E. Lucangioli, Martin F. Desimone, Sabrina FlorAbstract:Increasing bacterial resistance calls for the simultaneous delivery of multiple Antibiotics. One strategy is to design a unique pharmaceutical carrier that is able to incorporate several drugs with different physico-chemical properties. This is highly challenging as it may require the development of compartmentalization approaches. Here we have prepared core–shell silica particles allowing for the dual delivery of gentamicin and Rifamycin. The effect of silica particle surface functionalization on antibiotic sorption was first studied, enlightening the role of electrostatic and hydrophobic interactions. This in turn dictates the chemical conditions for shell deposition and further sorption of these Antibiotics. In particular, the silica shell deposition was favored by the positively charged layer of gentamicin coating on the core particle surface. Shell modification by thiol groups finally allowed for Rifamycin sorption. The antibacterial activity of the core–shell particles against Staphylococcus aureus and Pseudomonas aeruginosa demonstrated the dual release and action of the two Antibiotics.
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Silica core–shell particles for the dual delivery of gentamicin and Rifamycin Antibiotics
Journal of materials chemistry B, 2016Co-Authors: Andrea M. Mebert, Carole Aimé, Gisela S. Alvarez, Yupeng Shi, Sabrina A. Flor, Silvia E. Lucangioli, Martin F. Desimone, Thibaud CoradinAbstract:Increasing bacterial resistance calls for the simultaneous delivery of multiple Antibiotics. One strategy is to design a unique pharmaceutical carrier that is able to incorporate several drugs with different physico-chemical properties. This is highly challenging as it may require the development of compartmentalization approaches. Here we have prepared core–shell silica particles allowing for the dual delivery of gentamicin and Rifamycin. The effect of silica particle surface functionalization on antibiotic sorption was first studied, enlightening the role of electrostatic and hydrophobic interactions. This in turn dictates the chemical conditions for shell deposition and further sorption of these Antibiotics. In particular, the silica shell deposition was favored by the positively charged layer of gentamicin coating on the core particle surface. Shell modification by thiol groups finally allowed for Rifamycin sorption. The antibacterial activity of the core–shell particles against Staphylococcus aureus and Pseudomonas aeruginosa demonstrated the dual release and action of the two Antibiotics.
