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Emilio Bouza, Patricia Muñoz, Almudena Burillo
PURPOSE OF REVIEW: Tedizolid is a second-generation oxazolidinone with activity against Gram-positive bacteria, including MRSA isolates resistant to linezolid. Pivotal clinical trials showed that tedizolid at 200 mg once-daily for 6 days is not inferior to linezolid 600 mg twice daily for 10 days in patients with SSTI. The comparison of adverse events is favorable to tedizolid under the circumstances of the clinical trials. This is a review of recent literature on tedizolid, its use in special populations and potential adverse effects...
January 15, 2018: Current Opinion in Infectious Diseases
Joan Guasch, Irene Giménez, Ignacio Funes-Ardoiz, Isabel Matheu, Feliu Maseras, Sergio Castillón, Yolanda Díaz, Miguel Bernús
Regio- and stereoselective oxyamination of dienes through a tandem rhodium catalysed aziridination-nucleophilic opening affords racemic oxazolidinone derivatives, which undergo a kinetic resolution acylation process using ABCs (amidine-based catalysts) achieving s values up to 117. This protocol was applied to the enantioselective synthesis of sphingosine.
January 17, 2018: Chemistry: a European Journal
N Lokesh, Andreas Seegerer, Johnny Hioe, Ruth M Gschwind
The low sensitivity of NMR and transient key intermediates below detection limit are the central problems studying reaction mechanisms by NMR. Sensitivity can be enhanced by hyperpolarization techniques such as dynamic nuclear polarization or the incorporation/interaction of special hyperpolarized molecules. However, all of these techniques require special equipment, are restricted to selective reactions or undesirably influence the reaction pathways. Here, we apply the Chemical Exchange Saturation Transfer (CEST) technique for the first time to NMR detect and characterize previously unobserved transient reaction intermediates in organocatalysis...
January 16, 2018: Journal of the American Chemical Society
Engeline van Duijkeren, Anne-Kathrin Schink, Marilyn C Roberts, Yang Wang, Stefan Schwarz
During the past decades resistance to virtually all antimicrobial agents has been observed in bacteria of animal origin. This chapter describes in detail the mechanisms so far encountered for the various classes of antimicrobial agents. The main mechanisms include enzymatic inactivation by either disintegration or chemical modification of antimicrobial agents, reduced intracellular accumulation by either decreased influx or increased efflux of antimicrobial agents, and modifications at the cellular target sites (i...
January 2018: Microbiology Spectrum
Ruoyi Hua, Yun Xia, Wenyao Wu, Jia Yan, Mi Yang
Linezolid is an oxazolidinone antibiotic commonly used to treat serious infections caused by vancomycin-resistant enterococcus. Recently, low-level linezolid resistant Enterococcus faecalis strains have emerged worldwide, but the resistant mechanisms remain undefined. Whole-transcriptome profiling was performed on an E. faecalis strain P10748 with low-level linezolid resistance in comparison with a linezolid-susceptible strain 3138 and the standard control strain ATCC29212. The functions of differentially expressed genes (DEGs) were predicted, with some DEGs potentially involved in drug resistance were validated by PCR and quantitative PCR (qPCR)...
January 8, 2018: Gene
Erico S Loreto, Juliana S M Tondolo, Daniele C Oliveira, Janio M Santurio, Sydney H Alves
We tested 29 isolates of Pythium insidiosum and one isolate of Pythium aphanidermatum to investigate their susceptibility to miltefosine and antibacterial drugs from macrolide, oxazolidinone, and pleuromutilin classes. We found that miltefosine, azithromycin, clarithromycin, josamycin, linezolid, sutezolid, retapamulin, tiamulin, and valnemulin had inhibitory and cidal activity against the pathogens at concentrations ranging from 0.25 to 64 μg/ml. Our results suggest that these antimicrobials are promising candidates for future studies on pythiosis in animals and humans...
January 8, 2018: Antimicrobial Agents and Chemotherapy
Fadi Aldeek, Kevin Hsieh, Obiadada Ugochukwu, Ghislain Gerard, Walter Hammack
We developed and validated a method for the extraction, identification, and quantitation of four nitrofuran metabolites: (3-amino-2-oxazolidinone (AOZ); 3-amino-5-morpholinomethyl-2-oxazolidinone (AMOZ); semicarbazide (SC); and 1-aminohydantoin (AHD)), as well as chloramphenicol and florfenicol, in a variety of seafood commodities. Samples were extracted by liquid-liquid extraction techniques, analyzed by UHPLC-MS/MS, and quantitated using commercially sourced, derivatized nitrofuran metabolites, with their isotopically-labelled internal standards in-solvent...
December 28, 2017: Journal of Agricultural and Food Chemistry
Zhu-Bao Yin, Jian-Heng Ye, Wen-Jun Zhou, Yi-Han Zhang, Li Ding, Yong-Yuan Gui, Si-Shun Yan, Jing Li, Da-Gang Yu
A selective oxy-difluoroalkylation of allylamines with carbon dioxide (CO2) via visible-light photoredox catalysis is reported. These multicomponent reactions are efficient and environmentally friendly to generate a series of important 2-oxazolidinones with functionalized difluoroalkyl groups. The good functional group tolerance, broad substrate scope, easy scalability, mild reaction conditions, and facile functionalization of products provide great potential for application in organic synthesis and pharmaceutical chemistry...
December 27, 2017: Organic Letters
Tatsuya Ishikawa, Tomoko Kawasaki-Takasuka, Toshio Kubota, Takashi Yamazaki
As an extension of the boron enolate-based aldol reactions, the oxazolidinone-installed bisimide 1a from 3-(trifluoromethyl)glutaric acid was employed for Mannich reactions with tosylated imines 2 as electrophiles to successfully obtain the corresponding adducts in a stereoselective manner.
2017: Beilstein Journal of Organic Chemistry
Vishnu C Damalanka, Yunjeong Kim, Anushka C Galasiti Kankanamalage, Athri D Rathnayake, Nurjahan Mehzabeen, Kevin P Battaile, Scott Lovell, Harry Nhat Nguyen, Gerald H Lushington, Kyeong-Ok Chang, William C Groutas
Acute nonbacterial gastroenteritis caused by noroviruses constitutes a global public health concern and a significant economic burden. There are currently no small molecule therapeutics or vaccines for the treatment of norovirus infections. A structure-guided approach was utilized in the design of a series of inhibitors of norovirus 3CL protease that embody an oxazolidinone ring as a novel design element for attaining optimal binding interactions. Low micromolar cell-permeable inhibitors that display anti-norovirus activity have been identified...
December 6, 2017: European Journal of Medicinal Chemistry
J Zhu, J Hu, Y F Mao, F Y Chen, J Y Zhu, J M Shi, D D Yu, S G Hao, R Tao, P Liu, S Y Gu, J Hou, H Y He, A B Liang, Y Ding, L G Liu, Y H Xie, Q Zhu, Y H Yu, Y H Yao, W Chen, H L Xu, X H Han, C Wang
Objective: To investigate the pathogen spectrum distribution and drug resistance of febrile neutropenic patients with hematological diseases in Shanghai. Methods: A retrospective study was conducted on the clinical isolates from the febrile neutropenic patients hospitalized in the departments of hematology in 12 general hospitals in Shanghai from January 2012 to December 2014. The drug susceptibility test was carried out by Kirby-Bauer method. WHONET 5.6 software was used to analyze pathogenic bacteria and drug susceptibility data...
November 14, 2017: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
Fabrice Compain, Daria Soroka, Beate Heym, Jean-Louis Gaillard, Jean-Louis Herrmann, Delphine Dorchène, Michel Arthur, Vincent Dubée
Infections due to Mycobacterium abscessus carry a poor prognosis since this rapidly growing mycobacterium is intrinsically resistant to most antibiotics. Here, we evaluate the in vitro activity of the new oxazolidinone tedizolid against a collection of 44M. abscessus clinical isolates. The MIC50s and MIC90s of tedizolid (2 and 8μg/mL, respectively) were 2- to 16-fold lower than those of linezolid. There was no difference between the 3M. abscessus subspecies. Time-kill assays did not show any bactericidal activity at 4- and 8-fold the MIC...
November 10, 2017: Diagnostic Microbiology and Infectious Disease
Christopher G McPherson, Alasdair K Cooper, Andrius Bubliauskas, Paul Mulrainey, Craig Jamieson, Allan J B Watson
An organobase-mediated multicomponent reaction of unactivated esters, epoxides, and amines is reported, furnishing functionalized amide derivatives. A wide range of substrates are tolerated under the reaction conditions, including chiral epoxides, which react with no erosion of enantiopurity. Facile modification of the method through replacing the ester derivative with dimethyl carbonate enables access to the corresponding oxazolidinone derivatives.
December 1, 2017: Organic Letters
Zong Chang, France Boyaud, Régis Guillot, Thomas Boddaert, David J Aitken
Short gram scale syntheses of both enantiomers of 2-amino-3-hydroxycyclobutane-1-carboxylic acid and of 2-amino-4-hydroxycyclobutanecarboxylic acid with an all-cis geometry are described. The sequences feature highly endo-selective [2+2]-photocycloaddition reactions followed by fully regioselective ring opening / Hofmann rearrangement / nitrogen protection, in a consecutive or one-pot protocol, followed by efficient resolution using a chiral oxazolidinone.
December 1, 2017: Journal of Organic Chemistry
Sang-Hun Oh, Hee-Soo Park, Jun-Hyung Lee, Sung-Yun Baek, Sang-Eun Chae, Kyuman Oh, Young Lag Cho, Jin-Hwan Kwak
LCB01-0648 is a novel oxazolidinone compound that shows potent antibacterial activities against most Gram-positive cocci, including the multi-drug resistant Staphylococcusaureus. In this study, in vivo activity of LCB01-0699, a LCB01-0648 prodrug, against S.aureus was evaluated in comparison with that of Linezolid. The results of the systemic infection study demonstrated that LCB01-0699 was more potent than Linezolid against methicillin-susceptible and -resistant S. aureus strains. The in vivo efficacy of LCB01-0699 against methicillin-susceptible and -resistant S...
November 29, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Etienne Ruppé, Abdessalam Cherkaoui, Vladimir Lazarevic, Stéphane Emonet, Jacques Schrenzel
Clinical metagenomics (CMg), referred to as the application of next-generation sequencing (NGS) to clinical samples, is a promising tool for the diagnosis of hospital-acquired pneumonia (HAP). Indeed, CMg allows identifying pathogens and antibiotic resistance genes (ARGs), thereby providing the information required for the optimization of the antibiotic regimen. Hence, provided that CMg would be faster than conventional culture, the probabilistic regimen used in HAP could be tailored faster, which should lead to an expected decrease of mortality and morbidity...
November 29, 2017: Antibiotics
Xiaoming Yang, Yu Zhao, Min-Tsang Hsieh, Guang Xin, Rong-Tsun Wu, Pei-Lun Hsu, Lin-Yea Horng, Hui-Ching Sung, Chien-Hsin Cheng, Kuo-Hsiung Lee
(+)-Medicarpin has been synthesized asymmetrically for the first time in a linear scalable process with an overall yield of 11%. The two chiral centers were constructed in one step via condensation using a chiral oxazolidinone auxiliary. This method will likely accelerate research on medicarpin as an erythropoietin inducer for erythropoietin-deficient diseases.
November 22, 2017: Journal of Natural Products
Mahesh S Deshmukh, Nidhi Jain
A series of novel oxazolidinone antibacterials with diverse fused heteroaryl C-rings bearing hydrogen bond donor and hydrogen bond acceptor functionalities were designed and synthesized. The compound with benzoxazinone C-ring substructure (8c) exhibited superior activity compared to linezolid against a panel of Gram-positive and Gram-negative bacteria. Structural modifications at C5-side chain of 8c resulted in identification of several potent compounds (12a, 12b, 12g, and 12h). Selected compounds 8c and 12a showed very good microsomal stability and no CYP450 liability, thus clearing preliminary safety hurdles...
November 9, 2017: ACS Medicinal Chemistry Letters
Run Fan, Dexi Li, Andrea T Feßler, Congming Wu, Stefan Schwarz, Yang Wang
A novel transferable oxazolidinone-phenicol resistance gene, optrA, which confers resistance to linezolid, the next-generation oxazolidinone tedizolid, and also to chloramphenicol and florfenicol, has been identified in enterococcal and staphylococcal species. Here, we investigated the epidemiology of optrA in florfenicol-resistant Staphylococcus spp. isolates of pig origin, and characterized the genetic context of oxazolidinone resistance genes in 20 optrA-positive florfenicol- and methicillin-resistant S...
October 2017: Veterinary Microbiology
Andrew Spaulding, Khuloud Takrouri, Pornachandran Mahalingam, Dillon C Cleary, Harold D Cooper, Paola Zucchi, Westley Tear, Bilyana Koleva, Penny J Beuning, Elizabeth B Hirsch, James B Aggen
Previously we reported the results from an effort to improve Gram-negative antibacterial activity in the oxazolidinone class of antibiotics via a systematic medicinal chemistry campaign focused entirely on C-ring modifications. In that series we set about testing if the efflux and permeation barriers intrinsic to the outer membrane of Escherichia coli could be rationally overcome by designing analogs to reside in specific property limits associated with Gram-negative activity: i) low MW (<400), ii) high polarity (clogD7...
October 16, 2017: Bioorganic & Medicinal Chemistry Letters
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