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https://www.readbyqxmd.com/read/29325167/a-multicentre-study-of-antifungal-susceptibility-patterns-among-350-candida-auris-isolates-2009-17-in-india-role-of-the-erg11-and-fks1-genes-in-azole-and-echinocandin-resistance
#1
Anuradha Chowdhary, Anupam Prakash, Cheshta Sharma, Milena Kordalewska, Anil Kumar, Smita Sarma, Bansidhar Tarai, Ashutosh Singh, Gargi Upadhyaya, Shalini Upadhyay, Priyanka Yadav, Pradeep K Singh, Vikas Khillan, Neelam Sachdeva, David S Perlin, Jacques F Meis
Background: Candida auris has emerged globally as an MDR nosocomial pathogen in ICU patients. Objectives: We studied the antifungal susceptibility of C. auris isolates (n = 350) from 10 hospitals in India collected over a period of 8 years. To investigate azole resistance, ERG11 gene sequencing and expression profiling was conducted. In addition, echinocandin resistance linked to mutations in the C. auris FKS1 gene was analysed. Methods: CLSI antifungal susceptibility testing of six azoles, amphotericin B, three echinocandins, terbinafine, 5-flucytosine and nystatin was conducted...
January 9, 2018: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/29320899/in-vitro-analysis-of-itraconazole-cis-diastereoisomers-inhibition-of-nine-cytochrome-p450-enzymes-stereoselective-inhibition-of-cyp3a
#2
Kristyna Krasulova, Zdenek Dvorak, Pavel Anzenbacher
Itraconazole (ITZ), an antifungal azole derivate is a chiral drug that consists of four cis-diastereoisomers ((+)-2R,4S,2'R-ITZ-A; (+)-2R,4S,2'S-ITZ-B; (-)2S,4R,2'S-ITZ-C and (-) 2S,4R,2'R-ITZ-D) which may differ in their pharmacokinetics and pharmacodynamics. As itraconazole is known as a CYP3A4 inhibitor causing severe drug-drug interaction, the inhibitory potencies of its individual optical isomers towards nine drug-metabolising cytochrome P450 (including CYP3A, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2E1), were investigated...
January 10, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29319709/displacement-of-%C3%AE-5-cyclopentadienyl-ligands-from-half-sandwich-c-c-nhc-cyanoalkyl-nickel-ii-metallacycles-further-insight-into-the-structure-of-the-resulting-cp-free-nickelacycles-and-a-catalytic-activity-study
#3
Bernardo de P Cardoso, Jean-Marie Bernard-Schaaf, Saurabh Shahane, Luis F Veiros, Michael J Chetcuti, Vincent Ritleng
Four cationic C,C-(NHC-cyanoalkyl)-nickel(ii) metallacyclic complexes, [Ni{Me-NHC-CH2CH(CN)}(NCMe)](PF6) (2a), [Ni{Mes-NHC-CH2CH(CN)}(NCMe)](PF6) (2b), [Ni{Mes-NHC-(CH2)2CH(CN)}(NCMe)](PF6) (2c) and [Ni{DiPP-NHC-(CH2)2CH(CN)}(NCMe)](PF6) (2d), were prepared by the removal of the Cp ligand under acidic conditions at 0 °C from the corresponding half-sandwich nickelacycles [NiCp{R-NHC-(CH2)nCH(CN)}] (1a-1d; Cp = η5-C5H5; n = 1 or 2; R-NHC-(CH2)nCH(CN) = 1-R-3-[(CH2)nCH(CN)]-imidazol-2-ylidene). Full characterization of 2a-d by 1H and 13C{1H} NMR spectroscopy in CD3CN and pyridine-d5, ATR-FTIR spectroscopy, mass spectrometry, and CHN microanalyses established the presence of only one acetonitrile ligand per nickel atom in the solid state...
January 10, 2018: Dalton Transactions: An International Journal of Inorganic Chemistry
https://www.readbyqxmd.com/read/29311090/investigation-of-multiple-resistance-mechanisms-in-voriconazole-resistant-aspergillus-flavus-clinical-isolates-from-a-chest-hospital-surveillance-in-delhi-india
#4
Cheshta Sharma, Rakesh Kumar, Nitin Kumar, Aradhana Masih, Dinesh Gupta, Anuradha Chowdhary
Invasive and allergic infections by Aspergillus flavus are more common in tropical and subtropical countries. The emergence of voriconazole (VRC) resistance in A. flavus impacts the management of aspergillosis as azoles are used as the first line and empiric therapy. We screened molecularly confirmed 120 A. flavus isolates obtained from respiratory and sino-nasal specimens in a chest hospital in Delhi for azole resistance using CLSI BMD method. Overall, 2.5% (n=3/120) of A. flavus isolates had VRC MICs above epidemiological cutoff values (>1μg/ml)...
January 8, 2018: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29311085/the-rim-pathway-mediates-antifungal-tolerance-in-candida-albicans-through-newly-identified-rim101-transcriptional-targets-including-hsp90-and-ipt1
#5
Cécile Garnaud, Encar García-Oliver, Yan Wang, Danièle Maubon, Sébastien Bailly, Quentin Despinasse, Morgane Champleboux, Jérôme Govin, Muriel Cornet
Invasive candidiasis (IC) is a major cause of morbidity and mortality despite antifungal treatment. Azoles and echinocandins are used as first-line therapies in IC. However, their efficacy is limited by yeast tolerance and the emergence of acquired resistance. Tolerance is a reversible stage due to the yeast's capacity to counter the antifungal drug exposure, leading to persistent growth. In C. albicans, multiple stress signaling pathways have been shown to contribute to this adaptation. Among those, the Rim pH-responsive pathway, through its transcription factor Rim101p, was shown to mediate azole and echinocandin tolerance...
January 8, 2018: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29311083/aspergillus-fumigatus-afssn3-afssn8-pair-reverse-regulates-azole-resistance-by-conferring-extracellular-polysaccharide-sphingolipid-pathway-intermediates-and-efflux-pumps-to-biofilm
#6
Nanbiao Long, Liping Zeng, Shanlei Qiao, Lei Li, Guowei Zhong
Antifungal treatment is often ineffectual, which is partly contributed by biofilm. In this study, combined forward and reverse genetics strategy, we identified the nucleus-localized AfSsn3 and its partner AfSsn8, which constituting a cdk8-cyclin pair, are required for azole resistance in Aspergillus fumigatus Deletion of Afssn3 led to increased absorption and utilization of glucose and amino acids. Interestingly, absorption and utilization of glucose accelerated the extracellular polysaccharide formation, while utilization of the amino acids serine, threonine and glycine increased sphingolipid pathway intermediates accumulation...
January 8, 2018: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29311082/deletion-of-ada2-increases-antifungal-drug-susceptibility-and-virulence-in-candida-glabrata
#7
Shang-Jie Yu, Ya-Lin Chang, Ying-Lien Chen
Candida glabrata, the second most frequent cause of candidiasis after Candida albicans, is an emerging human fungal pathogen that is intrinsically drug tolerant. Currently, studies of C. glabrata genes involved in drug tolerance are limited. Ada2, a component serving as a transcription adaptor of the Spt-Ada-Gcn5 acetyltransferase (SAGA) complex, is required for antifungal drug tolerance and virulence in C. albicans However, its roles in C. glabrata remain elusive. In this study, we found that ada2 mutants demonstrated severe growth defects at 40°C but only mild defects at 37°C or 25°C...
January 8, 2018: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29304213/echinocandin-prophylaxis-in-patients-undergoing-haematopoietic-cell-transplantation-and-other-treatments-for-haematological-malignancies
#8
David J Epstein, Susan K Seo, Janice M Brown, Genovefa A Papanicolaou
Antifungal prophylaxis is the standard of care for patients undergoing intensive chemotherapy for haematological malignancy or haematopoietic cell transplantation (HCT). Prophylaxis with azoles reduces invasive fungal infections and may reduce mortality. However, breakthrough infections still occur, and the use of azoles is sometimes complicated by pharmacokinetic variability, drug interactions, adverse events and other issues. Echinocandins are highly active against Candida species, including some organisms resistant to azoles, and have some clinical activity against Aspergillus species as well...
January 1, 2018: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/29304211/we-can-do-better-a-fresh-look-at-echinocandin-dosing
#9
Justin C Bader, Sujata M Bhavnani, David R Andes, Paul G Ambrose
First-line antifungal therapies are limited to azoles, polyenes and echinocandins, the former two of which are associated with high occurrences of severe treatment-emergent adverse events or frequent drug interactions. Among antifungals, echinocandins present a unique value proposition given their lower rates of toxic events as compared with azoles and polyenes. However, with the emergence of echinocandin-resistant Candida species and the fact that a pharmacometric approach to the development of anti-infective agents was not a mainstream practice at the time these agents were developed, we question whether echinocandins are being dosed optimally...
January 1, 2018: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/29300681/physical-chemical-properties-and-cell-toxicity-of-sanding-copper-treated-lumber
#10
Jennifer D Sisler, Chaolong Qi, Walter McKinney, Justine Shaffer, Michael Andrew, Taekhee Lee, Treye Thomas, Vincent Castranova, Robert R Mercer, Yong Qian
To protect against decay and fungal invasion into the wood, the micronized copper, copper carbonate particles, has been applied in the wood treatment in recent years; however, there is little information on the health risk associated with sanding micronized copper- treated lumber. In this study, wood dust from the sanding of micronized copper azole -treated lumber (MCA) was compared to sanding dust from solubilized copper azole-treated wood (CA-C) and untreated yellow pine (UYP). The test found that sanding MCA released a much higher concentration of nanoparticles than sanding CA-C and UYP, and the particles between about 0...
January 4, 2018: Journal of Occupational and Environmental Hygiene
https://www.readbyqxmd.com/read/29288706/improved-vaginal-retention-and-enhanced-antifungal-activity-of-miconazole-microsponges-gel-formulation-development-and-in-vivo-therapeutic-efficacy-in-rats
#11
Salwa Salah, Ghada E A Awad, Amal I A Makhlouf
Traditional azole antifungal formulations suffer from poor retention in the vaginal cavity, irritation and burning of the vaginal area. In the present work, we aim at the development of a novel miconazole (MCZ) microsponges gel as an attractive dosage form for vaginal candidiasis. The proposed formula has the potential to minimize the local side effects of the drug due to the controlled release characteristic, which increases patient compliance. Moreover, the mucosal retention effect of the microsponges in addition to the bioadhesion property of Carbopol gel prolongs the retention of the dosage form in the vagina and consequently improves the therapeutic efficiency...
December 27, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/29284029/cyp51-is-an-essential-drug-target-for-the-treatment-of-primary-amoebic-meningoencephalitis-pam
#12
Anjan Debnath, Claudia M Calvet, Gareth Jennings, Wenxu Zhou, Alexander Aksenov, Madeline R Luth, Ruben Abagyan, W David Nes, James H McKerrow, Larissa M Podust
Primary Amoebic Meningoencephalitis (PAM) is caused by Naegleria fowleri, a free-living amoeba that occasionally infects humans. While considered "rare" (but likely underreported) the high mortality rate and lack of established success in treatment makes PAM a particularly devastating infection. In the absence of economic inducements to invest in development of anti-PAM drugs by the pharmaceutical industry, anti-PAM drug discovery largely relies on drug 'repurposing'-a cost effective strategy to apply known drugs for treatment of rare or neglected diseases...
December 2017: PLoS Neglected Tropical Diseases
https://www.readbyqxmd.com/read/29279242/novel-fluconazole-derivatives-with-promising-antifungal-activity
#13
Nishad Thamban Chandrika, Sanjib K Shrestha, Huy X Ngo, Kaitlind C Howard, Sylvie Garneau-Tsodikova
The fungistatic nature and toxicity concern associated with the azole drugs currently on the market have resulted in an increased demand for new azole antifungal agents for which these problematic characteristics do not exist. The extensive use of azoles has resulted in fungal strains capable of resisting the action of these drugs. Herein, we report the synthesis and antifungal activity of novel fluconazole (FLC) analogues with alkyl-, aryl-, cycloalkyl-, and dialkyl-amino substituents. We evaluated their antifungal activity by MIC determination and time-kill assay as well as their safety profile by hemolytic activity against murine erythrocytes as well as cytotoxicity against mammalian cells...
December 17, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29261092/recognition-of-azole-resistant-aspergillosis-by-physicians-specializing-in-infectious-diseases-united-states
#14
Tiffany A Walker, Shawn R Lockhart, Susan E Beekmann, Philip M Polgreen, Scott Santibanez, Rajal K Mody, Karlyn D Beer, Tom M Chiller, Brendan R Jackson
Infections caused by pan-azole-resistant Aspergillus fumigatus strains have emerged in Europe and recently in the United States. Physicians specializing in infectious diseases reported observing pan-azole-resistant infections and low rates of susceptibility testing, suggesting the need for wider-scale testing.
January 2018: Emerging Infectious Diseases
https://www.readbyqxmd.com/read/29251506/scanning-quadrupole-data-independent-acquisition-part-b-application-to-the-analysis-of-the-calcineurin-interacting-proteins-during-treatment-of-aspergillus-fumigatus-with-azole-and-echinocandin-antifungal-drugs
#15
Praveen R Juvvadi, M Arthur Moseley, Christopher J Hughes, Erik J Soderblom, Sarah Lennon, Simon R Perkins, J Will Thompson, Scott J Geromanos, Jason Wildgoose, Keith Richardson, James I Langridge, Johannes P C Vissers, William J Steinbach
Calcineurin is a critical cell-signaling protein that orchestrates growth, stress response, virulence, and antifungal drug resistance in several fungal pathogens. Blocking calcineurin signaling increases the efficacy of several currently available antifungals and suppresses drug resistance. We demonstrate the application of a novel scanning quadrupole DIA method for the analysis of changes in the proteins coimmunoprecipitated with calcineurin during therapeutic antifungal drug treatments of the deadly human fungal pathogen Aspergillus fumigatus...
December 29, 2017: Journal of Proteome Research
https://www.readbyqxmd.com/read/29235363/phenotypic-screening-approaches-for-chagas-disease-drug-discovery
#16
Eric Chatelain, Jean-Robert Ioset
Introduction- Chagas disease, caused by the parasite Trypanosoma cruzi, is a global public health issue. Current treatments targeting the parasite are limited to two old nitroheterocyclic drugs with serious side effects. The need for new and safer drugs has prompted numerous drug discovery efforts to identify compounds suitable for parasitological cure in the last decade. Areas covered- Target-based drug discovery has been limited by the small number of well validated targets - the latest example being the failure of azoles, T...
December 13, 2017: Expert Opinion on Drug Discovery
https://www.readbyqxmd.com/read/29232638/engineering-a-self-sufficient-mycobacterium-tuberculosis-cyp130-by-gene-fusion-with-the-reductase-domain-of-cyp102a1-from-bacillus-megaterium
#17
Sandra Ortega Ugalde, Rosa A Luirink, Daan P Geerke, Nico P E Vermeulen, Wilbert Bitter, Jan N M Commandeur
CYP130 belongs to the subset of cytochrome P450s from Mycobacterium tuberculosis (Mtb) that have been structurally characterized. Despite several efforts for its functional characterization, CYP130 is still considered an orphan enzyme for which no endogenous or exogenous substrate has been identified. In addition, functional redox-partners for CYP130 have not been clearly established yet, hampering the elucidation of its physiological role. In the present study, a catalytically active fusion protein involving CYP130 and the NADPH reductase-domain of CYP102A1 from Bacillus megaterium was created...
December 7, 2017: Journal of Inorganic Biochemistry
https://www.readbyqxmd.com/read/29228331/clinical-characteristics-and-outcomes-of-patients-with-chronic-disseminated-candidiasis-who-need-adjuvant-corticosteroid-therapy
#18
Young-Rock Jang, Min-Chul Kim, Taeeun Kim, Yong Pil Chong, Sang-Oh Lee, Sang-Ho Choi, Yang Soo Kim, Jun Hee Woo, Jung Yong Hong, Dok Hyun Yoon, Cheolwon Suh, Jung-Hee Lee, Je-Hwan Lee, Kyoo-Hyung Lee, Sung-Han Kim
We performed a retrospective study involving 21 patients with chronic disseminate candidiasis (CDC) and 38 patients with candidemia. Neutropenia of >2 weeks' duration was more common in those with CDC (71%) than in those with candidemia (26%, P < .001), and the azole-resistant rate in patients with CDC (5%) was lower than that in those with candidemia (29%, P = .03). Of the 21 patients with CDC, five (24%) needed adjuvant corticosteroid therapy due to persistent debilitating fever (median, 19 days). Rapid defervescence (median, 5 days) occurred after adjuvant corticosteroid therapy...
December 8, 2017: Medical Mycology: Official Publication of the International Society for Human and Animal Mycology
https://www.readbyqxmd.com/read/29228287/azole-resistant-and-susceptible-aspergillus-fumigatus-isolates-show-comparable-fitness-and-azole-treatment-outcome-in-immunocompetent-mice
#19
Michaela Lackner, Günter Rambach, Emina Jukic, Bettina Sartori, Josef Fritz, Christoph Seger, Magdalena Hagleitner, Cornelia Speth, Cornelia Lass-Flörl
No data are available on the in vivo impact of infections with in vitro azole-resistant Aspergillus fumigatus in immunocompetent hosts. Here, the aim was to investigate fungal fitness and treatment response in immunocompetent mice infected with A. fumigatus (parental strain [ps]) and isogenic mutants carrying either the mutation M220K or G54W (cyp51A). The efficacy of itraconazole (ITC) and posaconazole (PSC) was investigated in mice, intravenously challenged either with a single or a combination of ps and mutants (6 × 105 conidia/mouse)...
December 8, 2017: Medical Mycology: Official Publication of the International Society for Human and Animal Mycology
https://www.readbyqxmd.com/read/29227471/inhibiting-mitochondrial-phosphate-transport-as-an-unexploited-antifungal-strategy
#20
Catherine A McLellan, Benjamin M Vincent, Norma V Solis, Alex K Lancaster, Lucas B Sullivan, Cathy L Hartland, Willmen Youngsaye, Scott G Filler, Luke Whitesell, Susan Lindquist
The development of effective antifungal therapeutics remains a formidable challenge because of the close evolutionary relationship between humans and fungi. Mitochondrial function may present an exploitable vulnerability because of its differential utilization in fungi and its pivotal roles in fungal morphogenesis, virulence, and drug resistance already demonstrated by others. We now report mechanistic characterization of ML316, a thiohydantoin that kills drug-resistant Candida species at nanomolar concentrations through fungal-selective inhibition of the mitochondrial phosphate carrier Mir1...
December 11, 2017: Nature Chemical Biology
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