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In this present work, a newly designed metal‐oxide nanoparticle incorporated Covalent organic framework (COF), CuxOy@TFP‐ODA has been successfully synthesized and used for the effective synthesis of Oxazolidinones and a‐hydroxy ketones under mild conditions utilizing CO2. Initially, imine‐linked 2D COF, TFP‐ODA was synthesized by simple solvothermal method followed by the embedment of copper oxide nanoparticles (NPs) into the skeleton of the as‐synthesized COF. Different characterization techniques were employed to establish the physical and chemical characteristics of both CuxOy@TFP‐ODA and TFP‐ODA COF materials. To study the catalytic efficiency of the highly porous CuxOy@TFP‐ODA, three components coupling reaction involving primary amine, propargyl alcohol and CO2 to synthesize a series of 2‐Oxazolidinone and synthesis of α‐hydroxy ketones using CO2 as a Co‐catalyst were carried out over the as‐prepared catalyst under green and sustainable conditions which illustrated excellent yields and selectivity of the corresponding products. The synthesized catalyst was proved to be completely heterogeneous and especially, the catalyst material demonstrated significant potential for reuse across several catalytic cycles. [ABSTRACT FROM AUTHOR]

The method for converting epoxy carbamates to oxazolidinones is outlined in this study. This innovative approach combines intermolecular nucleophilic epoxide ring opening with intramolecular acyl substitution in a single step, thereby facilitating rapid conversion. Significantly, this method effectively addresses challenges associated with the use of expensive reagents, harsh reaction conditions, and prolonged reaction times, presenting a more efficient alternative. Demonstrating favorable reactivity across a diverse range of aryl groups, as well as benzyl or tert‐butyl carbamates, the method consistently yields satisfactory results, with oxazolidinone formation ranging from 55 % to 99 % in over 24 examples. The synthesized oxazolidinones, including 5 v–5 x, hold substantial promise as intermediates for the synthesis of crucial synthetic molecules. Furthermore, the versatility of this method is underscored by its successful application in the formation of the 6‐membered ring 1,3‐oxazinan‐2‐one. These findings not only contribute to the advancement of synthetic methodologies but also pave the way for a streamlined synthesis of important pharmaceutical compounds. [ABSTRACT FROM AUTHOR]

Purpose: The principal objective of this project was to review and thoroughly examine the chemical characteristics, pharmacological activity, and quantification methods associated with contezolid. Methods: The article was based on published and ongoing preclinical and clinical studies on the application of contezolid. These studies included experiments on the physicochemical properties of contezolid, in vitro antimicrobial research, in vivo antimicrobial research, and clinical trials in various phases. There were no date restrictions on these studies. Results: In June 2021, contezolid was approved for treating complicated skin and soft tissue infections. The structural modification of contezolid has resulted in better efficacy compared to linezolid. It inhibits bacterial growth by preventing the production of the functional 70S initiation complex required to translate bacterial proteins. The current evidence has indicated a substantial decline in myelosuppression and monoamine oxidase inhibition without impairing its antibacterial properties. Contezolid was found to have a more significant safety profile and to be metabolised by flavin monooxygenase 5, reducing the risk of harmful effects due to drug–drug interactions. Adjusting doses is unnecessary for patients with mild to moderate renal or hepatic insufficiency. Conclusion: As an oral oxazolidinone antimicrobial agent, contezolid is effective against multi-drug resistant Gram-positive bacteria. The introduction of contezolid provided a new clinical option. [ABSTRACT FROM AUTHOR]

The structure of (S)-5-(3-acetyl-5-chloro-2-ethoxy-6-fluorophenyl)-2-oxazolidinone, C13H13ClFNO4, at 100 K has monoclinic (P21) symmetry. The compound has a polymeric structure propagated by a screw axis parallel to the b axis with N—H...O hydrogen bonding. It is of interest with respect to efforts in the synthesis of a candidate anticancer drug, parsaclisib.

Objectives: Linezolid is a last-resort antimicrobial in human clinical settings to treat multidrug-resistant Gram-positive bacterial infections. Mobile linezolid resistance genes (optrA, poxtA, and cfr) have been detected in various sources worldwide. However, the presence of linezolid-not-susceptible bacteria and mobile linezolid resistance genes in Japan remains uncertain. Therefore, we clarified the existence of linezolid-not-susceptible bacteria and mobile linezolid resistance genes in farm environments in Japan. Methods: Enterococci isolates from faeces compost collected from 10 pig and 11 cattle farms in Japan in 2021 were tested for antimicrobial susceptibility and possession of mobile linezolid resistance genes. Whole-genome sequencing of optrA and/or poxtA genes positive-enterococci was performed. Results: Of 103 enterococci isolates, 12 from pig farm compost were not-susceptible (2 resistant and 10 intermediate) to linezolid. These 12 isolates carried mobile linezolid resistance genes on plasmids or chromosomes (5 optrA-positive Enterococcus faecalis, 6 poxtA-positive E. hirae or E. thailandicus, and 1 optrA- and poxtA-positive E. faecium). The genetic structures of optrA- and poxA-carrying plasmids were almost identical to those reported in other countries. These plasmids were capable of transferring among E. faecium and E. faecalis strains. The optrA- and poxtA-positive E. faecium belonged to ST324 (clade A2), a high-risk multidrug-resistant clone. The E. faecalis carrying optrA gene on its chromosome was identified as ST593. Conclusions: Although linezolid is not used in livestock, linezolid-not-susceptible enterococci could be indirectly selected by frequently used antimicrobials, such as phenicols. Moreover, various enterococci species derived from livestock compost may serve as reservoirs of linezolid resistance genes carried on globally disseminated plasmids and multidrug-resistant high-risk clones.

The structure of (S)-5-(3-acetyl-5-chloro-2-ethoxy-6-fluorophenyl)-2-oxazolidinone, C13H13ClFNO4, at 100 K has monoclinic (P21) symmetry. The compound has a polymeric structure propagated by a screw axis parallel to the b axis with N--H⋯O hydrogen bonding. It is of interest with respect to efforts in the synthesis of a candidate anticancer drug, parsaclisib. [ABSTRACT FROM AUTHOR]

An unexpected diastereoselective C-alkylation of a mefloquine derivative in up to 57% yield was the result of an attempted Williamson etherification of Boc-mefloquine. The domino reaction involved oxazolidinone ring closure, deprotonation, and stereoselective carbon–carbon bond formation. The structure was confirmed with 2D NMR experiments. [ABSTRACT FROM AUTHOR]

In this contribution, we describe a straightforward and efficient synthesis of oxazolidin‐2‐ones through a Cu(I)‐catalyzed four‐component coupling of amines, aldehydes, terminal alkynes, and CO2 via carboxylative cyclization of propargylamine intermediates. This strategy enables the selective synthesis of a variety of (Z)‐5‐alkylidene‐oxazolidin‐2‐ones substituted in positions 3, 4 and 5 of the heterocyclic core with a variety of functional groups, well‐tolerated in terms of scope. A mechanistic study was carried out monitoring the process in solution by different techniques (operando FTIR, multi‐nuclear NMR), with the aim of identifying the intermediates, both organic compounds and Cu(I) coordination complexes, which showed the plausible multi‐metallic nature of the catalytic intermediates (identified by X‐ray diffraction analyses on monocrystal). [ABSTRACT FROM AUTHOR]

In the last decade, magnesium complexes have emerged as a viable alternative to transition‐metal catalysts for the hydrofunctionalization of unsaturated bonds. However, their potential for advanced catalytic reactions has not been thoroughly investigated. To address this gap, we have developed a novel magnesium amide compound (3) using a PNP framework that is both bulky and flexible. Our research demonstrates that compound 3 can effectively catalyze the synthesis of biologically significant oxazolidinone derivatives. This synthesis involves a tandem reaction of hydroalkoxylation and cyclohydroamination of isocyanate using propargyl alcohol. Furthermore, we conducted comprehensive theoretical calculations to gain insights into the reaction mechanism. It is important to note that these types of transformations have not been reported for magnesium and would significantly enhance the catalytic portfolio of the 7th most abundant element. [ABSTRACT FROM AUTHOR]

Introduction: Guillain-Barré Syndrome (GBS) is a neurological disorder associated with ascending paralysis due to damage to the peripheral nerves by the immune system. Hyponatremia is the most common electrolyte disorder encountered in patients with GBS admitted to the Neurointensive Care Unit (NICU). Hyponatremia is associated with a poor outcome, prolonged hospital stay, and increased hospital cost. Linezolid is an oxazolidinone antibiotic used against gram-positive bacteria. The main adverse effect limiting its use is the development of myelo suppression; however, it can also cause hyponatremia. Aim: To investigate the incidence of hyponatremia in GBS patients treated with linezolid. Materials and Methods: This was a retrospective study conducted in a 14-bedded NICU at the National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India, over a period from January 2017 to January 2018. All patients with GBS who received linezolid therapy were included in the study. Out of 46 admitted patients, 16 received linezolid therapy. Final data were available for 12 patients. Hyponatremia was defined as sodium

Introduction: Guillain-Barré Syndrome (GBS) is a neurological disorder associated with ascending paralysis due to damage to the peripheral nerves by the immune system. Hyponatremia is the most common electrolyte disorder encountered in patients with GBS admitted to the Neurointensive Care Unit (NICU). Hyponatremia is associated with a poor outcome, prolonged hospital stay, and increased hospital cost. Linezolid is an oxazolidinone antibiotic used against gram-positive bacteria. The main adverse effect limiting its use is the development of myelo suppression; however, it can also cause hyponatremia. Aim: To investigate the incidence of hyponatremia in GBS patients treated with linezolid. Materials and Methods: This was a retrospective study conducted in a 14-bedded NICU at the National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India, over a period from January 2017 to January 2018. All patients with GBS who received linezolid therapy were included in the study. Out of 46 admitted patients, 16 received linezolid therapy. Final data were available for 12 patients. Hyponatremia was defined as sodium <134 mmol/L, and severe hyponatremia was defined as sodium <128 mmol/L. Descriptive statistics were used to characterise the data. The Wilcoxon signed-rank test was used to compare sodium levels before and after linezolid therapy. A p-value <0.05 was considered significant. Results: The incidence of hyponatremia was 9 out of 12 (75%). Five out of 12 patients had severe hyponatremia. There was a significant decrease of 11 (7-12) mmol/L in sodium level before and after linezolid therapy (p<0.001). The median days to develop hyponatremia were 3 (2-4) days after initiation of therapy. No mortality was observed in the study population. Conclusion: The incidence of hyponatremia is high in GBS patients treated with linezolid in the NICU. It is imperative to monitor sodium levels at frequent intervals in patients treated with linezolid to recognise and treat hyponatremia. [ABSTRACT FROM AUTHOR]

Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are a global health concern. The propensity of MRSA to form biofilms is a significant contributor to its pathogenicity. Strategies to treat biofilms often involve small molecules that disperse the biofilm into planktonic cells. Linezolid and, by extension, theoxazolidinones have been developed to treat infections caused by Gram-positive bacteria such as MRSA. However, the clinical development of these antibiotics has mainly assessed the susceptibility of planktonic cells to the drug. Previous studies evaluating the anti-biofilm activity of theoxazolidinones have mainly focused on the biofilm inhibition of Enterococcus faecalis and methicillin-sensitive Staphylococcus aureus, with only a few studies investigating the activity of oxazolidinones for eradicating established biofilms for these species. Very little is known about the ability of oxazolidinones to eradicate MRSA biofilms. In this work, five oxazolidinones were assessed against MRSA biofilms using a minimum biofilm eradication concentration (MBEC) assay. All oxazolidinones had inherent antibiofilm activity. However, only ranbezolid could completely eradicate MRSA biofilms at clinically relevant concentrations. The susceptibility of the MRSA biofilms to ranbezolid was synergistically enhanced by coadministration with the nitroxide biofilm dispersal agent C-TEMPO. We presume that ranbezolid acts as a dual warhead drug, which combines the mechanism of action of the oxazolidinones with a nitric oxide donor or cytotoxic drug. [ABSTRACT FROM AUTHOR]

We report on the preparation of copper iodide nanoparticles (NPs) immobilized on vitamin B3-modified graphene (CuI/GO-VB) nanocomposite and its application for the synthesis of oxazolidinone compounds using a remarkable carboxylative cyclization method via the reaction of arylacetylene, aldehyde and benzylamine derivatives under an atmospheric pressure of CO2 gas. The CuI/GO-VB catalyst was prepared from graphene oxide (GO), vitamin B3 (VB) and CuI using a two-step procedure; firstly graphene-based composite (GO-VB) was synthesized by the reaction of GO and nicotinoyl chloride, followed by the immobilization of CuI NPs on GO-VB. The CuI/GO-VB nanocomposite was fully identified with X-ray diffraction (XRD), Fourier-transform infrared (FT-IR) spectroscopy, field emission scanning electron microscopy (FESEM), energy dispersive spectroscopy (EDS), inductively coupled plasma optical emission spectroscopy (ICP-OES), transmission electron microscopy (TEM), thermogravimetric analysis (TGA), and X-ray photoelectron spectroscopy (XPS). The catalytic performance of the CuI/GO-VB heterogeneous catalyst was investigated in carboxylative cyclization for the synthesis of oxazolidinone compounds under an atmospheric pressure of CO2 gas at 100οC in solvent-, base-, and additive-free conditions; the corresponding oxazolidinone compounds were obtained in 79–94% yield. The hot filtration results indicated that CuI/GO-VB nanocomposite was a heterogeneous catalyst and showed a good reusability for 5 runs without a significant decrease in its catalytic performance. [ABSTRACT FROM AUTHOR]

Objective To investigate the antibacterial activity of contezolid and linezolid against common Gram-positive bacteria and to preliminarily analyze the mechanism of their inhibition of biofilm. Methods Staphylococcus aureus (S. aureus) and Enterococcus faecalis (E. faecalis) were taken as the research objects. We used the broth dilution method to determine the minimum inhibitory concentration (MIC) of contezolid and linezolid against S. aureus and E. faecalis. The growth curve was used to detect the growth of bacteria under different drug concentrations, and the formation of bacterial biofilm and the survival rate of bacteria in the biofilm were observed by crystal violet staining under the drug concentration that did not inhibit the growth of bacteria. Proteomics was used to screen the differentially expressed proteins in the biofilm of Gram-positive bacteria under the action of contezolid and linezolid. Functional annotation of gene ontology (GO), Kyoto Encylopaedia of Genes and Genomes (KEGG), and protein interaction network (PPI) was used to observe the interaction between proteins. Results Contezolid and linezolid showed broad-spectrum antibacterial activity against S. aureus and E. faecalis, and their MICs were both less than 4 µg/mL. The growth curve showed that contezolid and linezolid at 1/2 × MIC had no effect on bacterial growth. The result of crystal violet staining and the count of viable bacteria in biofilm showed that both drugs could inhibit the formation of S. aureus and E. faecalis biofilm at sub-inhibitory concentration. There were 290 and 222 differentially expressed proteins in the biofilm of Gram-positive bacteria under the action of contezolid and linezolid. The differential proteins mainly involved Rpm, rplE, SasG, Luxs, ald 1, D-alanine aminotransferase, etc. GO analysis showed that the differentially expressed proteins were mainly related to pyruvate metabolism and amino acid metabolism under the action of contezolid. The differential expression of proteins under linezolid mainly involved pyrimidine metabolism, purine metabolism, amino acid metabolism, etc. KEGG analysis showed that the differentially expressed proteins treated with contezolid mainly involved in naphthalene degradation, pyrimidine metabolism, glycolysis, and ribosome excision and repair. The differentially expressed proteins treated with linezolid mainly involved amino acid degradation, fatty acid degradation, purine metabolism, pentose, and glucose phosphate conversion. PPI analysis showed that the differentially expressed proteins under the action of two antibiotics were mainly related to ribosomes. Conclusions Contezolid and linezolid show broad-spectrum antibacterial activity and biofilm inhibition against Grampositive bacteria. These two drugs may inhibit the formation of biofilm of Gram-positive bacteria by inhibiting quorum sensing system, primary metabolism and biofilm formation related genes. [ABSTRACT FROM AUTHOR]

Abstract Background Linezolid is an effective, but toxic anti-tuberculosis drug that is currently recommended for the treatment of drug-resistant tuberculosis. Improved oxazolidinones should have a better safety profile, while preserving efficacy. Delpazolid is a novel oxazolidinone developed by LegoChem Biosciences Inc. that has been evaluated up to phase 2a clinical trials. Since oxazolidinone toxicity can occur late in treatment, LegoChem Biosciences Inc. and the PanACEA Consortium designed DECODE to be an innovative dose-ranging study with long-term follow-up for determining the exposure–response and exposure–toxicity relationship of delpazolid to support dose selection for later studies. Delpazolid is administered in combination with bedaquiline, delamanid and moxifloxacin. Methods Seventy-five participants with drug-sensitive, pulmonary tuberculosis will receive bedaquiline, delamanid and moxifloxacin, and will be randomized to delpazolid dosages of 0 mg, 400 mg, 800 mg, 1200 mg once daily, or 800 mg twice daily, for 16 weeks. The primary efficacy endpoint will be the rate of decline of bacterial load on treatment, measured by MGIT liquid culture time to detection from weekly sputum cultures. The primary safety endpoint will be the proportion of oxazolidinone class toxicities; neuropathy, myelosuppression, or tyramine pressor response. Participants who convert to negative liquid media culture by week 8 will stop treatment after the end of their 16-week course and will be observed for relapse until week 52. Participants who do not convert to negative culture will receive continuation phase treatment with rifampicin and isoniazid to complete a six-month treatment course. Discussion DECODE is an innovative dose-finding trial, designed to support exposure-response modelling for safe and effective dose selection. The trial design allows assessment of occurrence of late toxicities as observed with linezolid, which is necessary in clinical evaluation of novel oxazolidinones. The primary efficacy endpoint is the change in bacterial load, an endpoint conventionally used in shorter dose-finding trials. Long-term follow-up after shortened treatment is possible through a safety rule excluding slow-and non-responders from potentially poorly performing dosages. Trial registration DECODE was registered in ClinicalTrials.gov before recruitment start on 22 October 2021 (NCT04550832).

An unexpected diastereoselective C-alkylation of a mefloquine derivative in up to 57% yield was the result of an attempted Williamson etherification of Boc-mefloquine. The domino reaction involved oxazolidinone ring closure, deprotonation, and stereoselective carbon–carbon bond formation. The structure was confirmed with 2D NMR experiments.

BackgroundContezolid is a novel oxazolidinone antibacterial agent, but there have been no reports of any pertinent clinical studies for the treatment of tuberculosis (TB). This was the first report of three TB patients who were successfully treated with contezolid.Case presentationCase 1 was TB complicated by myelosuppression syndrome. Case 2 was drug-resistant TB complicated by cirrhosis and anemia. Case 3 was drug-resistant TB complicated by liver transplantation that developed severe anemia after linezolid treatment. Following contezolid therapy, the three patients’ symptoms improved significantly, and no adverse reactions were observed. The chest computed tomography (CT) examination also indicated that the therapeutic effect of this anti-TB regimen was as expected.ConclusionContezolid showed good efficacy and fewer side effects in the treatment of TB. It may be a promising TB treatment.

The reaction with isocyanate gives noncyclized product first and the subsequent cyclization is presumed to give the desired oxazolidinone-2,3-fused indoline and azaindoline derivatives B 2 b . Keywords: 3-bromo-2-hydroxy-1-tosylindoline; 3-bromo-2-hydroxy-1-tosylazaindoline; oxazolidinone; isocyanate; cyclization EN 3-bromo-2-hydroxy-1-tosylindoline 3-bromo-2-hydroxy-1-tosylazaindoline oxazolidinone isocyanate cyclization 1603 1606 4 07/31/23 20230815 NES 230815 Graph Indoles, azaindoles, indolines, and azaindolines are important privileged structures present in several biologically active compounds, from both natural and synthetic pharmaceutical origins. [9] Herein, we report the design and syntheses of oxazolidinone-2,3-fused indoline and azaindoline derivatives B 2 b via one-pot cyclization with isocyanate B 3 b (Scheme 1). [Extracted from the article]

In the present work, a series of novel oxazolidinone derivatives containing thieno-pyridine ring system (11a–n) were synthesized in six steps. Synthesis of amino oxazolidinone scaffold (10) involved nucleophilic substitution of thienopyridine (4) with P-chloro-nitrobenzene (3) in dimethyl formamide at 65 °C give nitro compound (5) which was further reduced in catalytic hydrogenation condition using Raney-Nickel in isopropyl alcohol afforded amine (6). Reaction of compound (6) with 2-[(2S)-oxiran-2-ylmethyl]-1H-isoindole-1,3(2H)-dione (7) at mild reflux condition in isopropyl alcohol gives compound (8). Hydroxy amine compound (8) further undergo carbonyl insertion reaction with 1, 1'-carbonylbis(1H-imidazole) afforded oxazolidinone compound (9). The de-protection of phthalamide group of compound (9) carried by treating with aqueous solution of hydrazine hydrate in methanol at room temperature give compound (10). Finally, compound (10) reacts with acetyl chloride, carboxylic acid, sulfonyl chloride and chloro format by customary method provided amides, sulfonamide and carbamate derivative of (5S)-5-(aminomethyl)-3-[4-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)phenyl]-1,3-oxazolidin-2-one. The developed synthetic approach was operationally simple and high yielding. The structures of the synthesized compounds were elucidated by IR, MS, 1H and 13C-NMR. Synthesized compounds (11a–n) were tested for antibacterial activity against a panel of Gram-positive bacteria comprising Staphylococcus aureus (ATCC5638), Streptococcus pyogenes (ATCC12344), Bacillus subtilis (ATCC6051), Bacillus pumilus (ATCC27142), and Enterococcus faecalis (NCIM5253). The investigation of antimicrobial screening data revealed that, most of the compounds tested have demonstrated sensible to good bacterial activity. In summary, preliminary results of activity indicate that, acetyl derivative (11a), methane sulfonamide derivative (11c) and p-toluene sulfonamide derivative (11e) found to be good activity and di-(methane sulfonamide) derivative (11d) showed comparable activity to reference drug substances. [ABSTRACT FROM AUTHOR]

Catalytic reactions of 3-membered heterocycles, such as epoxides and aziridines, with CO2 in the presence of metal–salen complexes are considered in this review (salens is a class of ligands, derived from diamines and salicylaldehyde or its substituted analogs). These reactions lead to copolymers or cyclic carbonates/oxazolidinones, which are important products of modern fine and industrial organic synthesis. The influence of metal ion, substituents in salen and the nature of cocatalyst on the catalytic performance of the systems based on metal–salen complexes, reported during two recent decades, is analyzed. It was shown that formation of bi- or polynuclear complexes, as well as incorporation of the organic cocatalyst (such as tetraalkylammonium cation) in the molecule of the metal-containing catalyst improved the catalytic performance of metal–salen species due to cooperative effect on several active sites in activation of epoxide and its reaction with CO2. The ways for creation of heterogeneous metal–salen catalysts for reactions of 3-membered heterocycles with CO2 are also summarized. [ABSTRACT FROM AUTHOR]

Background: Linezolid is an effective, but toxic anti-tuberculosis drug that is currently recommended for the treatment of drug-resistant tuberculosis. Improved oxazolidinones should have a better safety profile, while preserving efficacy. Delpazolid is a novel oxazolidinone developed by LegoChem Biosciences Inc. that has been evaluated up to phase 2a clinical trials. Since oxazolidinone toxicity can occur late in treatment, LegoChem Biosciences Inc. and the PanACEA Consortium designed DECODE to be an innovative dose-ranging study with long-term follow-up for determining the exposure–response and exposure–toxicity relationship of delpazolid to support dose selection for later studies. Delpazolid is administered in combination with bedaquiline, delamanid and moxifloxacin. Methods: Seventy-five participants with drug-sensitive, pulmonary tuberculosis will receive bedaquiline, delamanid and moxifloxacin, and will be randomized to delpazolid dosages of 0 mg, 400 mg, 800 mg, 1200 mg once daily, or 800 mg twice daily, for 16 weeks. The primary efficacy endpoint will be the rate of decline of bacterial load on treatment, measured by MGIT liquid culture time to detection from weekly sputum cultures. The primary safety endpoint will be the proportion of oxazolidinone class toxicities; neuropathy, myelosuppression, or tyramine pressor response. Participants who convert to negative liquid media culture by week 8 will stop treatment after the end of their 16-week course and will be observed for relapse until week 52. Participants who do not convert to negative culture will receive continuation phase treatment with rifampicin and isoniazid to complete a six-month treatment course. Discussion: DECODE is an innovative dose-finding trial, designed to support exposure-response modelling for safe and effective dose selection. The trial design allows assessment of occurrence of late toxicities as observed with linezolid, which is necessary in clinical evaluation of novel oxazolidinones. The primary efficacy endpoint is the change in bacterial load, an endpoint conventionally used in shorter dose-finding trials. Long-term follow-up after shortened treatment is possible through a safety rule excluding slow-and non-responders from potentially poorly performing dosages. Trial registration: DECODE was registered in ClinicalTrials.gov before recruitment start on 22 October 2021 (NCT04550832). [ABSTRACT FROM AUTHOR]

Comparative chiral separations of enantiomeric pairs of four oxazolidinone and two related thio-derivatives were performed by capillary electrophoresis, using cyclodextrins (CDs) as chiral selectors. Since the selected analytes are neutral, the enantiodiscrimination capabilities of nine anionic CD derivatives were determined, in 50 mM phosphate buffer pH = 6. Unanimously, the most successful chiral selector was the single isomeric heptakis-(6-sulfo)-β-cyclodextrin (HS-β-CD), which resulted in the highest enantioresolution values out of the CDs applied for five of the six enantiomeric pairs. The enantiomer migration order (EMO) was the same for two enantiomeric pairs, irrespective of the CD applied. However, several examples of EMO reversals were obtained in the other cases. Interestingly, changing from randomly substituted, multi-component mixtures of sulfated-β-CD to the single isomeric chiral selector, enantiomer migration order reversal occurred for two enantiomeric pairs and similar observations were made when comparing heptakis-(2,3-di-O-methyl-6-O-sulfo)-β-CD, (HDMS-β-CD) with HS-β-CD. In several cases, cavity-size-dependent, and substituent-dependent EMO reversals were also observed. Minute differences in the structure of the analytes were also responsible for several cases of EMO reversal. The present study offers a complex overview of the chiral separation of structurally related oxazolidinones, and thio-analogs, highlighting the importance of the adequate choice of chiral selector in this group of compounds, where enantiomeric purity is of utmost importance. [ABSTRACT FROM AUTHOR]

Carbamate group is mainly used for designing prodrugs to achieve first‐pass and systemic stability against enzyme hydrolysis as the carbamate functionality is recognized by esterase enzymes. As compared to the ester functionality, the carbamate group shows a lesser lability towards enzyme hydrolysis, but a higher susceptibility than amides. Cyclic carbamates present a unique motif in the contemporary drug discovery and development owing to the presence of a polar, and sterically small, constrained Hydrogen‐bonding acceptor atom. The metabolic stability of 5/6‐membered cyclic carbamates are higher as compared to their acyclic counterparts as the former do not undergo metabolic ring opening under physiological conditions. Besides, the metabolic lability of acyclic carbamates is determined by the degree of substitution at the endocyclic/exocyclic "N" atom, which further enables the design and development of various carbamate drugs or prodrugs. As such, the metabolic stability of carbamates follows the order: Cyclic carbamates > Alkyl‐OCO‐NH2 » Alkyl‐OCO‐NHAcyl ∼ Alkyl‐OCO‐NHAryl ≥ Aryl‐OCO‐N(endocyclic) ∼ Aryl‐OCO‐N(Alkyl)2 ≥ Alkyl‐OCO‐N(endocyclic) ≥ Alkyl‐OCO‐N(Alkyl)2 ∼ Alkyl‐OCO‐NHAlkyl » Aryl‐OCO‐NHAlkyl. [ABSTRACT FROM AUTHOR]

Graphitic carbon nitride (g‐CN) is a transition metal free semiconductor that mediates a variety of photocatalytic reactions. Although photoinduced electron transfer is often postulated in the mechanism, proton‐coupled electron transfer (PCET) is a more favorable pathway for substrates possessing X−H bonds. Upon excitation of an (sp2)N‐rich structure of g‐CN with visible light, it behaves as a photobase—it undergoes reductive quenching accompanied by abstraction of a proton from a substrate. The results of modeling allowed us to identify active sites for PCET—the 'triangular pockets' on the edge facets of g‐CN. We employ excited state PCET from the substrate to g‐CN to selectively cleavethe endo‐(sp3)C−H bond in oxazolidine‐2‐ones followed by trapping the radical with O2. This reaction affords 1,3‐oxazolidine‐2,4‐diones. Measurement of the apparent pKa value and modeling suggest that g‐CN excited state can cleave X−H bonds that are characterized by bond dissociation free energy (BDFE) ≈100 kcal mol−1. [ABSTRACT FROM AUTHOR]

The mounting evidence of bacterial resistance against commonly prescribed antibiotics warrants the development of new antibacterial drugs on an urgent basis. Linezolid, an oxazolidinone antibiotic, is a lead molecule in designing new oxazolidinones as antibacterial agents. In this study, we report the antibacterial potential of the novel oxazolidinone-sulphonamide/amide conjugates that were recently reported by our research group. The antibacterial assays showed that, from the series, oxazolidinones 2 and 3a exhibited excellent potency (MIC of 1.17 μg/mL) against B. subtilis and P. aeruginosa strains, along with good antibiofilm activity. Docking studies revealed higher binding affinities of oxazolidinones 2 and 3a compared to linezolid, which were further validated by molecular dynamics simulations. In addition to this, other computational studies, one-descriptor (log P) analysis, ADME-T and drug likeness studies demonstrated the potential of these novel linezolid-based oxazolidinones to be taken forward for further studies. [ABSTRACT FROM AUTHOR]

Huiyun Zhang,1 Wenya Hua,1 Siran Lin,1 Yu Zhang,1 Xinchang Chen,1 Shiyong Wang,1 Jiazhen Chen,1 Wenhong Zhang1– 3 1Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China; 2National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China; 3Key Laboratory of Medical Molecular Virology (MOE/MOH), Shanghai Medical College, Fudan University, Shanghai, People’s Republic of ChinaCorrespondence: Jiazhen Chen, Department of Infectious Diseases, Huashan Hospital, Fudan University, Rm 524, Building No. 5, No. 12 Middle Wulumuqi Road, Shanghai, 200040, People’s Republic of China, Email jiazhen_chen@163.comObjective: Nontuberculous mycobacteria (NTM) can cause pulmonary and extrapulmonary diseases. Tedizolid (TZD) is a new oxazolidinone with in vitro activity against NTM such as Mycobacterium avium complex (MAC), Mycobacterium fortuitum, and Mycobacterium abscessus complex. The aim of this study was to evaluate the TZD susceptibility profiles of clinical isolates of NTM.Methods: The microdilution method was used to identify the minimum inhibitory concentration (MIC) of TZD and linezolid (LZD) for 133 clinical NTM isolates. Broth microdilution chequerboard assays were used to investigate the synergistic effects of TZD and three antibiotics on two reference isolates and eleven clinical isolates of NTM.Results: The TZD MIC50 and MIC90 for M. abscessus complex were 2 and 4 μg/mL, 16 and > 32 μg/mL for MAC, respectively. TZD exhibited lower MICs than that of LZD for most NTM, which were positively correlated. Due to the high MIC values of TZD against MAC, it is necessary to conduct drug sensitivity tests before TZD administration. TZD-clarithromycin combination had synergistic response on M. abscessus complex in 3 of the 8 isolates, which lasted only 3– 5 days. TZD-cefoxitin had synergistic effect against all five M. fortuitum isolates.Conclusion: Our study demonstrates that TZD had greater in vitro potency than LZD, and synergy studies suggested that TZD may be an important component of multi-drug treatment regimen.Keywords: tedizolid, susceptibility testing, nontuberculous mycobacteria, linezolid, oxazolidinone

The reactions of the diiron aminocarbyne complexes [Fe2Cp2(NCMe)(CO)(μ-CO){μ-CN(Me)(R)}]CF3SO3 (R = Me, 1aNCMe; R = Cy, 1bNCMe), freshly prepared from the tricarbonyl precursors 1a–b, with primary amines containing an additional function (i.e., alcohol or ether) proceeded with the replacement of the labile acetonitrile ligand and formation of [Fe2Cp2(NH2CH2CH2OR')(CO)(μ-CO){μ-CN(Me)(R)}]CF3SO3 (R = Me, R' = H, 2a; R = Cy, R' = H, 2b; R = Cy, R' = Me, 2c) in 81–95% yields. The diiron-oxazolidinone conjugate [Fe2Cp2(NH2OX)(CO)(μ-CO){μ-CN(Me)2}]CF3SO3, 3, was prepared from 1a, 3-(2-aminoethyl)-5-phenyloxazolidin-2-one (NH2OX) and Me3NO, and finally isolated in 96% yield. In contrast, the one pot reactions of 1a-b with NHEt2 in the presence of Me3NO gave the unstable [Fe2Cp2(NHEt2)(CO)(μ-CO){μ-CN(Me)(R)}]CF3SO3 (R = Me, 4a; R = Cy, 4b) as unclean products. All diiron complexes were characterized by analytical and spectroscopic techniques; moreover, the behavior of 2a–c and 3 in aqueous media was ascertained. [ABSTRACT FROM AUTHOR]

A series of Zn(II) complexes with oxazolidinone derivatives has been synthesized and characterized using spectroscopic techniques: IR, 1H NMR, UV-Vis spectroscopy, and TGA/DTG thermal investigation. Theoretical computations were carried out using B3LYP/6-31G(d) and B3LYP/LanL2DZ to analyze the vibrational properties, NBO charges, global chemical reactivity indices and to illustrate the FOMs. TD-DFT calculations using WB97XD functional were realized with 6-31 G(d) and LAN2DZ basis set on oxazolidinone ligands and their zinc complexes. The pharmacokinetic properties and toxicity of the investigated compounds were predicted using in silico ADMET studies. Moreover, the S. aureus, E. coli, S. pneumoniae, ribosome 50S subunit, SARS-Cov-2 spike protein and ACE2 human receptor were selected for molecular docking study. The docking study shows that HL4 and ZnL4 bind better to the spike protein and hACE2 receptor. The redox properties were also studied for ligands and their corresponding complexes using cyclic voltammetry. Finally, antioxidant activity studies using DPPH radical scavenging showed efficiency for HL2 and [Zn(L2)2] with low values of IC50 compared to ascorbic acid. The antimicrobial activity against B. subtilis (ATCC 9372), E. faecalis (ATCC 29212), S. aureus (ATCC 6538), E. coli (ATCC 4157), bacteria strains, C. albicans (ATCC 24433) and A. niger fungi strains were evaluated. [ABSTRACT FROM AUTHOR]

Cycloaddition of carbon dioxide (CO2) with aziridine catalyzed by a zinc‐salen having B−N coordinated phenanthroimidazole motif as a photocatalyst (1), at 1 bar CO2 pressure and room temperature under solvent free condition is presented. The photocatalyst exhibited excellent selectivity and tolerates a variety of substituted aziridines, and successfully produces the corresponding oxazolidinones at mild conditions. [ABSTRACT FROM AUTHOR]

The protonation of commercially available porphyrin ligands yields a class of bifunctional catalysts able to promote the synthesis of N‐alkyl oxazolidinones by CO2 cycloaddition to corresponding aziridines. The catalytic system does not require the presence of any Lewis base or additive, and shows interesting features both in terms of cost effectiveness and eco‐compatibility. The metal‐free methodology is active even with a low catalytic loading of 1 % mol, and the chemical stability of the protonated porphyrin allowed it to be recycled three times without any decrease in performance. In addition, a DFT study was performed in order to suggest how a simple protonated porphyrin can mediate CO2 cycloaddition to aziridines to yield oxazolidinones. [ABSTRACT FROM AUTHOR]

We have synthesized a new hybrid material, Ag0@CTFN in which small-sized Ag-nanoparticles (Ag-NPs) are anchored on the surface of covalent triazine framework nanosheet (CTFN). Here, CTFN works as the support as well as the capping agent for the small-sized Ag-NPs. Ag0@CTFN has been synthesized in a one pot method where Ag-NPs attach with the nitrogen atoms present in the triazin units. This as synthesized Ag0@CTFN material has been characterized by FTIR, XRD, N 2 adsorption desorption analysis, SEM, TEM and XPS analysis. All these characterizations reveal that around 4.97 nm sized Ag-NPs are anchored on the surfaces of layer-like CTFN nanosheets. Ag0@CTFN samples have shown their excellent catalytic activity for the selectively oxazolidinone formation from propargyl alcohol and amine by fixing CO 2 under mild reaction condition. Moreover, this is the first report on Ag0@CTFN hybrid material which catalyze the oxazolidinone synthesis by fixing CO 2. Again, this catalyst has shown their recyclability for oxazolidinone synthesis reaction up to sixth cycle by keeping their activity almost intact. There is no metal or catalyst leaching noticed up to sixth cycle for this reaction. AgNPs decorated Porous polymeric framework was constructed and employed as an efficient reusable heterogeneous catalyst for the synthesis of oxazolidinone from propargyl alcohol and amines by fixing CO 2 under very mild reaction conditions. [Display omitted] • We have synthesized Ag0@CTFN, in which small-sized Ag-nanoparticles are anchored on the surface of covalent triazine framework nanosheet (CTFN). Here, CTFN works as the support as well as the capping agent for the small-sized Ag-NPs. • Moreover, this is the first report in which small-sized Ag-nanoparticles (Ag-NPs) are anchored on the surface of covalent triazine framework nanosheet (CTFN). • The hybrid material, Ag0@CTFN was characterized by FTIR, PXRD, SEM, TEM, N 2 -adsorption desorption, XPS analysis. • The Ag0@CTFN samples showed excellent catalytic activity for the selectively oxazolidinone formation from propargyl alcohol and amine by fixing CO 2 under mild reaction condition. • This Ag0@CTFN acts as a heterogeneous catalyst that can be easily separated from the reaction mixture for reuse. [ABSTRACT FROM AUTHOR]

Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are a global health concern. The propensity of MRSA to form biofilms is a significant contributor to its pathogenicity. Strategies to treat biofilms often involve small molecules that disperse the biofilm into planktonic cells. Linezolid and, by extension, theoxazolidinones have been developed to treat infections caused by Gram-positive bacteria such as MRSA. However, the clinical development of these antibiotics has mainly assessed the susceptibility of planktonic cells to the drug. Previous studies evaluating the anti-biofilm activity of theoxazolidinones have mainly focused on the biofilm inhibition of Enterococcus faecalis and methicillin-sensitive Staphylococcus aureus, with only a few studies investigating the activity of oxazolidinones for eradicating established biofilms for these species. Very little is known about the ability of oxazolidinones to eradicate MRSA biofilms. In this work, five oxazolidinones were assessed against MRSA biofilms using a minimum biofilm eradication concentration (MBEC) assay. All oxazolidinones had inherent antibiofilm activity. However, only ranbezolid could completely eradicate MRSA biofilms at clinically relevant concentrations. The susceptibility of the MRSA biofilms to ranbezolid was synergistically enhanced by coadministration with the nitroxide biofilm dispersal agent C-TEMPO. We presume that ranbezolid acts as a dual warhead drug, which combines the mechanism of action of the oxazolidinones with a nitric oxide donor or cytotoxic drug.

Introduction: Staphylococcus aureus (S. aureus) is a ubiquitous pathogen causing various infections in humans. The emergence of drug resistance in S. aureus, especially methicillin resistance, has made treating these infections increasingly tricky, with only a few antibiotics being effective. Vancomycin, Teicoplanin, and Linezolid are the antibiotics of choice for treating Methicillin-resistant Staphylococcus aureus (MRSA) infections, though occasional resistance to these antibiotics has also been reported. Aim: To know the prevalence of MRSA and subject the MRSA isolates to linezolid and teicoplanin susceptibility testing by Epsilometer test (E-test). Materials and Methods: This was a cross-sectional study done between April 2021 and March 2022. A total of 210 consecutive S. aureus isolates from various clinical samples were isolated and processed in the Department of Microbiology, Andhra Medical College, Visakhapatnam, Andhra Pradesh, India. Screening for methicillin resistance was done by cefoxitin disc diffusion testing and Chromogenic agar (CHROMagar) MRSA, with American Type Culture Collection (ATCC) S. aureus 25923 strain as a negative control and a known in-house strain was used as a positive control. All the MRSA isolates were tested for linezolid and teicoplanin susceptibility for the E-test to determine the Minimum Inhibitory Concentration (MIC). Data were entered into Microsoft Excel 2019, and International Business Machines (IBM) Statistical Package for the Social Sciences (SPSS) version 20.0 was used for analysis. Results: Out of 210 S. aureus, 100 (47.6%) were MRSA isolates. MRSA was predominantly isolated from pus (58%), sputum (19%), and urine (9%) samples. Higher resistance was observed against cotrimoxazole (72%), ciprofloxacin (54%), and amikacin (37%). Teicoplanin and linezolid were both susceptible in all of the isolates. MIC50 and MIC90 against linezolid and teicoplanin was 0.5 and 1 mcg/mL and 0.5 and 0.75 μg/mL respectively. Conclusion: MRSA isolates are increasingly becoming resistant to multiple antibiotics. Linezolid and glycopeptides are still the mainstays for treating MRSA infections, as most isolates are susceptible to these drugs.

We reported herein the synthesis and antibacterial activity evaluation of two oxazolidinone-deferasirox conjugates with different linkers that were designed based on the "Trojan horse" strategy. The conjugates could combine with Fe3+ ions as the deferasirox. However, both conjugates were inactive against tested bacteria, including S. aureus, E. coli, A. baumannii, and P. aeruginosa. The results suggested that the synthesized iron chelator deferasirox was not suitable as a siderophore of the bacteria to transport the antibiotic, or the coupling linker of the synthesized conjugates could not be hydrolyzed to release the oxazolidinone in the cytoplasm. Therefore, the design and synthesis of oxazolidinone-deferasirox conjugates need further exploration. Keywords: Oxazolidinone; Deferasirox; Antibacterial; Siderophore; "Trojan horse" strategy [ABSTRACT FROM AUTHOR]

The preparation of new, enantiomerically pure, α-amino acids from easily available starting materials is an ongoing challenge in synthetic organic chemistry. Here, we describe the syntheses and crystal structures of three chiral oxazolidinone derivatives prepared from L-alanine and pivalaldehyde to form a Schiff base intermediate and then reaction with the appropriate acid chloride to form the heterocycle. In each compound, the methyl and tert-butyl substituents lie to the same side of the molecule: these homochiral 'cis' structures were separated from their trans diastereomers by fractional crystallisation. The five-membered rings in these structures adopt various conformations including envelopes with either a C or O atom as the flap and twisted about a C–O bond. The extended structures of two of these compounds feature C(6) chains of molecules linked by C–H···O hydrogen bonds: one of these has a notably short H···O separation of 2.24 (3) Å. [ABSTRACT FROM AUTHOR]

Antibiotic resistance genes (ARGs) as a novel type of environmental pollutant pose a health risk to humans. Oxazolidinones are one of the most important antibiotics for the treatment of Gram-positive bacterial infections in humans. Although oxazolidinones are not utilized in the livestock industry, florfenicol is commonly used on farms to treat bacterial infections, which may contribute to the spread of the cfr, optrA, and poxtA genes on farms. Using metagenomics sequencing, we looked into the antibiotic resistome context of florfenicol and oxazolidinone in 10 large-scale commercial farms in China. We identified 490 different resistance genes and 1,515 bacterial genera in the fecal samples obtained from 10 farms. Florfenicol-resistant Kurthia, Escherichia, and Proteus were widely present in these samples. The situation of florfenicol and oxazolidone resistance in pig farms is even more severe. The total number of genes and the abundance of drug resistance genes were higher in pigs than in chickens, including optrA and poxtA. All the samples we collected had a high abundance of fexA and floR. Through nanopore metagenomic analysis of the genetic environment, we found that plasmids, integrative and conjugative element (ICE), and transposons (Tn7-like and Tn558) may play an important role in the spread of floR, cfr, and optrA. Our findings suggest that florfenicol and oxazolidinone resistance genes have diverse genetic environments and are at risk of co-transmission with, for example, tetracycline and aminoglycoside resistance genes. The spread of florfenicol- and oxazolidinone-resistant bacteria on animal farms should be continuously monitored. [ABSTRACT FROM AUTHOR]

The appearance of transferable oxazolidinone resistance genes poses a major challenge to public health and environmental safety. These genes not only lead pathogenic bacteria to become resistant to linezolid but also reduce sensitivity to florfenicol, which is widely used in the veterinary field. To verify the dissemination of oxazolidinone resistance genes in enterococcal isolates from pigs at different production stages in a swine farm in China, we collected 355 enterococcal isolates that were resistant to florfenicol from 600 (150 per stage) fresh fecal swabs collected from a swine farm. Through initial PCR screening and whole-genome sequencing, 175 isolates harboring different oxazolidinone resistance genes were identified. All isolates carried the optrA gene. A total of 161 (92%, 161/175) isolates carried only the optrA gene. Three (1.71%, 3/175) isolates carried both the optrA and poxtA genes, and 11 (3.1%, 11/175) isolates contained the optrA gene and poxtA2 and cfr(D) variants. A total of 175 isolates that harbored oxazolidinone resistance genes included 161 E. faecalis, 6 E. faecium, and 8 E. hirae. By sequencing the whole genomes, we found that the 161 isolates of E. faecalis belonged to 28 different STs, including 8 new STs, and the 6 isolates of E. faecium belonged to four different STs, including one new ST. The phylogenetic tree based on SNPs of the core genome showed that both clonal spread and horizontal transfer mediated the diffusion of oxazolidone resistance genes in enterococcal isolates at specific stages in pig farms. Moreover, enterococcal isolates carrying oxazolidone resistance genes could spread from breeding pigs to fattening pigs, while transferable oxazolidone resistance genes in enterococcal isolates could persist on a pig farm throughout all production stages. Representative enterococcal isolates with different oxazolidinone resistance genes were further studied through Nanopore sequencing. We identified a novel plasmid, pM4-80L4 (15,008bp), carrying the poxtA2 and cfr(D) genes in enterococcal isolates at different stages. We also found three different plasmids harboring the poxtA gene with high genetic variation, and all poxtA genes were flanked by two copies of IS1216E elements. In addition, four genetically distinct plasmids carrying the optrA gene were identified, and Tn554 was found to mediate chromosome-localized optrA gene transfer. Our study highlighted that transferable oxazolidinone resistance genes in enterococcal isolates could persist throughout all production stages on a pig farm, and the prevalence and dissemination of oxazolidinone resistance genes in enterococcal isolates from animal farms should be continually monitored. [ABSTRACT FROM AUTHOR]

ObjectiveTo investigate the in vitro activities of five oxazolidinones in parallel against the reference strains of different mycobacterial species and clinical isolates of Mycobacterium tuberculosis (Mtb), and shed light on the differences in the efficacy of these homolog drugs.Materials and methodsThe minimum inhibitory concentrations (MICs) of linezolid, tedizolid, sutezolid, delpazolid, and contezolid against 16 mycobacterial reference strains and 69 M. tuberculosis clinical isolates, including 17 drug-susceptible isolates and 52 multidrug-resistant (MDR) isolates, were determined by microplate alamarBlue assay (MABA). The intracellular killing activities of contezolid and linezolid against Mtb H37Rv were compared. In addition, mutations in the linezolid resistance-related genes (rplC, rplD, and 23S rRNA) of the Mtb clinical isolates were also analyzed.ResultsTedizolid exhibited the strongest inhibitory activities against the reference strains of both rapidly growing mycobacteria (RGM) and slowly growing mycobacteria (SGM), among the tested oxazolidinones. In contrast, sutezolid only manifested potent activity against reference strains of SGM. Linezolid, delpazolid, and contezolid were less active against the non-tuberculous mycobacterial references. For the Mtb clinical isolates, the antimicrobial action was ranked as: sutezolid > tedizolid > contezolid and linezolid > delpazolid, whereas no difference between drug-sensitive and multiple drug-resistant isolates was observed. Notably, contezolid demonstrated obviously superior intracellular antimicrobial activity than linezolid. Few strains harbored mutations in rrl gene or rplD genes, although these strains had drug susceptible profiles to linezolid.ConclusionDifferent oxazolidinones can have discrepant antimicrobial activity against different mycobacterial species, or have different manifestations out of cell or in cell. Understanding these differences would be helpful in choosing the appropriate drug in clinical practice.

Florfenicol is widely used for the treatment of bacterial infections in domestic animals. The aim of this study was to analyze the molecular mechanisms of florfenicol and oxazolidinone resistance in Enterococcus isolates from anal feces of domestic animals. The minimum inhibitory concentration (MIC) levels were determined by the agar dilution method. Polymerase chain reaction (PCR) was performed to analyze the distribution of the resistance genes. Whole-genome sequencing and comparative plasmid analysis was conducted to analyze the resistance gene environment. A total of 351 non-duplicated enteric strains were obtained. Among these isolates, 22 Enterococcus isolates, including 19 Enterococcus. faecium and 3 Enterococcus. faecalis, were further studied. 31 florfenicol resistance genes (13 fexA, 3 fexB, 12 optrA, and 3 poxtA genes) were identified in 15 of the 19 E. faecium isolates, and no florfenicol or oxazolidinone resistance genes were identified in 3 E. faecalis isolates. Whole-genome sequencing of E. faecium P47, which had all four florfenicol and oxazolidinone resistance genes and high MIC levels for both florfenicol (256mg/L) and linezolid (8mg/L), revealed that it contained a chromosome and 3 plasmids (pP47-27, pP47-61, and pP47-180). The four florfenicol and oxazolidinone resistance genes were all related to the insertion sequences IS1216 and located on two smaller plasmids. The genes fexB and poxtA encoded in pP47-27, while fexA and optrA encoded in the conjugative plasmid pP47-61. Comparative analysis of homologous plasmids revealed that the sequences with high identities were plasmid sequences from various Enterococcus species except for the Tn6349 sequence from a Staphylococcus aureus chromosome (MH746818.1). The current study revealed that florfenicol and oxazolidinone resistance genes (fexA, fexB, poxtA, and optrA) were widely distributed in Enterococcus isolates from animal in China. The mobile genetic elements, including the insertion sequences and conjugative plasmid, played an important role in the horizontal transfer of florfenicol and oxazolidinone resistance. [ABSTRACT FROM AUTHOR]

In this paper, we report a mechanistic study of RuO4-catalyzed oxidation on the 2-methylisoxazolidine through computational methods. The investigation was performed taken into consideration that the oxidation could take place on different sites of the substrate. This reaction occurs in two steps, involving a double H-transfer. In particular, the rate-determining one implies a [3 + 2] one-step, but asynchronous mechanism. In the first step, when methyl propanoate is used as solvent, the formation of an ion pair, which affords to the product, is involved. Furthermore, the study highlights that all carbon atoms of the isoxazolidine system, near to the heteroatoms, can undergo the oxidation process. The detected selectivity is correlated to the stability of the corresponding carbocations, leading to the N-methylisoxazolidin-3-one as preferred product.

Objectives: The antimicrobial activity of tedizolid and comparators was evaluated against a large worldwide collection of Staphylococcus aureus and Streptococcus pneumoniae isolates recovered from patients with pneumonia. Methods: Clinical isolates were collected from patients in 96 medical centres in the Asia-Pacific region, Europe, Latin America and the USA between 2017 and 2019, and tested for susceptibility by reference broth microdilution. Results: The most active agents against S. aureus (n = 4667) were tedizolid (100.0% susceptible), linezolid (100.0% susceptible), ceftaroline (96.2% susceptible) and vancomycin (100.0% susceptible), but only tedizolid, linezolid and vancomycin retained activity against >95% of meticillin-resistant S. aureus isolates from all regions. In general, linezolid, ceftriaxone, ceftaroline, levofloxacin, penicillin and vancomycin showed susceptibility rates >95% against S. pneumoniae (n = 3008). However, only linezolid, ceftaroline, levofloxacin and vancomycin remained active (>95% susceptibility) against isolates displaying penicillin-non-susceptible or multidrug-resistant phenotypes. Penicillin-non-susceptible S. pneumoniae isolates were recovered less frequently from patients aged

Comparative chiral separations of enantiomeric pairs of four oxazolidinone and two related thio-derivatives were performed by capillary electrophoresis, using cyclodextrins (CDs) as chiral selectors. Since the selected analytes are neutral, the enantiodiscrimination capabilities of nine anionic CD derivatives were determined, in 50 mM phosphate buffer pH = 6. Unanimously, the most successful chiral selector was the single isomeric heptakis-(6-sulfo)-β-cyclodextrin (HS-β-CD), which resulted in the highest enantioresolution values out of the CDs applied for five of the six enantiomeric pairs. The enantiomer migration order (EMO) was the same for two enantiomeric pairs, irrespective of the CD applied. However, several examples of EMO reversals were obtained in the other cases. Interestingly, changing from randomly substituted, multi-component mixtures of sulfated-β-CD to the single isomeric chiral selector, enantiomer migration order reversal occurred for two enantiomeric pairs and similar observations were made when comparing heptakis-(2,3-di-O-methyl-6-O-sulfo)-β-CD, (HDMS-β-CD) with HS-β-CD. In several cases, cavity-size-dependent, and substituent-dependent EMO reversals were also observed. Minute differences in the structure of the analytes were also responsible for several cases of EMO reversal. The present study offers a complex overview of the chiral separation of structurally related oxazolidinones, and thio-analogs, highlighting the importance of the adequate choice of chiral selector in this group of compounds, where enantiomeric purity is of utmost importance.

[Display omitted] • A known sialyl thioglycoside was converted to the corresponding oxazolidinone derivative. • Further chemical modification of the oxazolidinone afforded the precursor Neu5Gc derivative. • Glycosidation of the thioglycoside with various simple alcohols yielded the desired α-glycosides in good yields. • Structural elucidation of the glycosides was performed by 1H NMR, 13C NMR, and HMBC. An efficient synthesis of lauryl thioglycoside of oxazolidinones derived from N -acetyl neuraminic acid was accomplished from a known thioglycoside of Neu5Ac. The O -glycosidation reactivities of the oxazolidinones were evaluated by means of trimethylsilyl trifluoromethanesulfonate (TMSOTf) and N -iodosuccinimide (NIS) as a combined-mediator system. The glycosidation reaction of the lauryl thioglycoside with simple alcohols proceeded smoothly to yield the corresponding α-glycosides in good yields after isolation. The results suggested that the glycosylation reaction using the oxazolidinone derivative of sialic acid has excellent α-stereoselectivity and enables easy isolation of the desired product from the reaction mixture. [ABSTRACT FROM AUTHOR]

Biofilms are part of the natural lifecycle of bacteria and are known to cause chronic infections that are difficult to treat. Most antibiotics are developed and tested against bacteria in the planktonic state and are ineffective against bacterial biofilms. The oxazolidinones, including the last resort drug linezolid, are one of the main classes of synthetic antibiotics progressed to clinical use in the last 50 years. They have a unique mechanism of action and only develop low levels of resistance in the clinical setting. With the aim of providing insight into strategies to design more potent antibiotic compounds with activity against bacterial biofilms, we review the biofilm activity of clinically approved oxazolidinones and report on structural modifications to oxazolidinones and their delivery systems which lead to enhanced anti‐biofilm activity. [ABSTRACT FROM AUTHOR]