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1.
Future Med Chem ; 14(15): 1149-1165, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35866418

RESUMO

Tuberculosis (TB) is an infectious and fatal disease caused by Mycobacterium tuberculosis (Mtb) and remains a serious public health threat; therefore, the development of new antitubercular agents is a priority for the World Health Organization's End TB strategy and the United Nations' Sustainable Development Goals to eradicate TB. Oxazolidinones are a class of synthetic antibacterial agents with a distinct mode of action developed for the treatment of Gram-positive bacterial infections. Many oxazolidinones exhibit good activity against Mtb, and some are currently in clinical trials for multidrug-resistant TB and extensively drug-resistant TB therapy. In this review, the mechanism of action, activity and toxicity of oxazolidinones and recent progress in the research and development of oxazolidinones as anti-TB agents are summarized.


Assuntos
Mycobacterium tuberculosis , Oxazolidinonas , Tuberculose Resistente a Múltiplos Medicamentos , Tuberculose , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Humanos , Oxazolidinonas/farmacologia , Oxazolidinonas/uso terapêutico , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico
2.
Biol Pharm Bull ; 45(7): 824-833, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35786589

RESUMO

The target therapeutic ranges of vancomycin, teicoplanin, and arbekacin have been determined, and therapeutic drug monitoring (TDM) is performed in clinical practice. However, TDM is not obligatory for daptomycin, linezolid, or tedizolid. In this study, we examined whether TDM will be necessary for these 3 drugs in the future. There was no significant difference in therapeutic effects on acute bacterial skin and skin structure infection between linezolid and tedizolid by meta-analysis. Concerning the therapeutic effects on pneumonia, the rate of effectiveness after treatment with tedizolid was significantly lower than with linezolid. With respect to safety, the incidences of gastrointestinal adverse events and blood/lymphatic system disorders related to tedizolid were significantly lower than those related to linezolid. Linezolid exhibits potent therapeutic effects on pneumonia, but the appearance of adverse reactions is indicated as a problem. There was a dose-dependent decrease in the platelet count, and the target trough concentration (Ctrough) was estimated to be 4-6 or 2-7 µg/mL in accordance with the patient's condition. The efficacy of linezolid may be obtained while minimizing the appearance of adverse reactions by performing TDM. The target therapeutic range of tedizolid cannot be achieved in immunocompromised or severe patients. Therefore, we concluded that TDM was unnecessary, considering step-down therapy with oral drugs, use in non-severe patients, and high-level safety. Concerning daptomycin, high-dose administration is necessary to achieve an area under the curve (AUC) of ≥666 as an index of efficacy. To secure its safety, Ctrough (<20 µg/mL) monitoring is important. Therefore, TDM is necessary.


Assuntos
Daptomicina , Daptomicina/efeitos adversos , Monitoramento de Medicamentos , Humanos , Linezolida/efeitos adversos , Oxazolidinonas , Preparações Farmacêuticas , Tetrazóis
3.
Drugs Today (Barc) ; 58(7): 315-326, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35851867

RESUMO

Contezolid (MRX-I, Youxitai) is an oral oxazolidinone drug being developed by MicuRx Pharmaceutical Co., Ltd., Shanghai, China. It was approved by China's National Medical Products Administration (NMPA) in June 2021, attaining its first approval for the treatment of complicated skin and soft tissue infections (cSSTIs). It is also under clinical development for acute bacterial skin and skin structure infections (ABSSSIs) in the U.S. after receiving qualified infectious disease product (QIDP) classification and fast track status by U.S. Food and Drug Administration (FDA) in September 2018. Contezolid is effective against a broad range of Gram-positive bacteria including activity against methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae and vancomycin-resistant Enterococci (VRE). It provides a major benefit over the most popular drug of its class, linezolid (Zyvox), by offering an improved safety profile and minimal effects concerning myelosuppression and monoamine oxidase (MAO) inhibition, two independent adverse events limiting linezolid use in the clinic. The recommended dosage regimen of contezolid is 800 mg every 12 hours for 7-14 days with regular food intake and it can be extended if required. At the mentioned dose under fed conditions, satisfactory efficacy against MRSA with a 90%; or higher cumulative fraction of response and probability of target attainment was achieved. Additionally, contezolid also exhibits activity against Mycobacterium tuberculosis and Mycobacterium abscessus.


Assuntos
Staphylococcus aureus Resistente à Meticilina , Oxazolidinonas , Infecções dos Tecidos Moles , Antibacterianos/efeitos adversos , China , Humanos , Linezolida/farmacologia , Linezolida/uso terapêutico , Oxazolidinonas/farmacologia , Oxazolidinonas/uso terapêutico , Piridonas , Infecções dos Tecidos Moles/induzido quimicamente , Infecções dos Tecidos Moles/complicações , Infecções dos Tecidos Moles/tratamento farmacológico , Estados Unidos
4.
Pediatr Infect Dis J ; 41(9): 731-735, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-35703275

RESUMO

BACKGROUND: Tedizolid was approved by the United States Food and Drug Administration to treat acute bacterial skin and skin structure infections in adults in 2014, and in 2020, United States Food and Drug Administration expanded the approval of tedizolid to treat pediatric patients 12 years of age and older. This study assessed the activity of tedizolid and comparator agents against clinical surveillance isolates collected from pediatric patients with skin and skin structure infection in the United States. METHODS: A total of 2747 gram-positive organisms (1 per patient) were collected in 2015 to 2019 from pediatric (≤17 years old) patients with skin and skin structure infections. The isolates were collected from 33 US medical centers and susceptibility tested against tedizolid and comparators by reference broth microdilution methods. Susceptibility results for main pathogens were stratified by patient age: ≤1 years old (851 isolates), 2 to 5 years old (623), 6 to 12 years old (754) and 13 to 17 years old (519). RESULTS: Staphylococcus aureus (n = 2163) was the main pathogen recovered from all age groups, followed by ß-hemolytic streptococci (n = 460). Tedizolid inhibited all S. aureus , including methicillin-resistant S. aureus (MRSA) isolates (41.0%), regardless of the age group. MRSA rates varied by age group; MRSA was highest among ≤1 years old (45.0%) and lowest in the 13 to 17 years old (32.7%) groups. Linezolid, daptomycin and vancomycin also displayed susceptibility rates of 100% against S. aureus isolates. Clindamycin (81.3%-98.5%), tetracycline (91.6%-97.1%) and trimethoprim-sulfamethoxazole (97.0%-100%) susceptibility rates varied among age groups and methicillin resistance profiles. Overall, tedizolid, linezolid, daptomycin and vancomycin inhibited all gram-positive pathogens in this collection. CONCLUSIONS: Tedizolid was very active against a large collection of gram-positive pathogens causing skin and skin structure infection in pediatric patients, including MRSA isolates.


Assuntos
Daptomicina , Staphylococcus aureus Resistente à Meticilina , Adolescente , Adulto , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Criança , Pré-Escolar , Hospitais , Humanos , Lactente , Linezolida/farmacologia , Testes de Sensibilidade Microbiana , Oxazolidinonas , Staphylococcus aureus , Tetrazóis , Estados Unidos/epidemiologia , Vancomicina/farmacologia
5.
Bioorg Med Chem Lett ; 71: 128842, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-35680102

RESUMO

Increased resistance to gram positive infections have highlighted the limitations of currently available drug treatments including penicillins, macrolides and glycopeptides. As an alternative to address these challenges; Linezolid, the first antibiotic from oxazolidinone class, have shown the promising activities against such infections, although associated toxicological issues limiting the use of linezolid for prolonged treatments. In order to circumvent disadvantages allied with the marketed drugs, we herein reporting the synthesis of WCK 4034, an oxazolidinone antibiotic through our structure activity relationship (SAR) program. Through this exercise, WCK 4034, has shown competitive MIC values against Methicillin Sensitive S. aureus (MSSA, Sta-001), Methicillin Resistant S. aureus (MRSA, Sta-032), S. pneumoniae ATCC 49619 and H. influenza ATCC 35054 species as like linezolid. Although with an additional advantage; WCK 4034 has been found superior during dog PK studies as compare to Linezolid. With the preliminary studies in our hand, we herein assuming these improved pharmacokinetic values would be helpful. Moreover, WCK 4034 has successfully completed pre-clinical studies and ready to enter the clinical space, and paved the way for in house development of other oxazolidinone NCEs.


Assuntos
Staphylococcus aureus Resistente à Meticilina , Oxazolidinonas , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Cães , Linezolida/farmacologia , Linezolida/uso terapêutico , Testes de Sensibilidade Microbiana , Oxazolidinonas/química , Oxazolidinonas/farmacologia , Oxazolidinonas/uso terapêutico , Staphylococcus aureus , Streptococcus pneumoniae
6.
Microb Drug Resist ; 28(7): 773-779, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35727074

RESUMO

Dispersion of transferable oxazolidinone resistance genes among enterococci poses a serious problem to human health. Prompt detection of bacteria carrying these genes is crucial to avoid their spread to multidrug-resistant bacteria. The aim of the study was to describe the presence of optrA-positive isolates among enterococci in a Spanish hospital, and to determine their genetic context and location through whole genome sequencing. All enterococci recovered in a Spanish hospital (Hospital El Bierzo; HEB) from February to December 2018 (n = 443), with minimal inhibitory concentrations (MICs) to linezolid (LZD) ≥4 mg/L, were tested by polymerase chain reaction for the presence of cfr, optrA, and poxtA transferable genes. Only four Enterococcus faecalis isolates (0.9%) had LZD MICs ≥4 mg/L and none of them was positive for cfr or poxtA genes. However, the optrA gene was detected in three isolates collected from urine samples of community patients, whose genomes were sequenced and subjected to bioinformatics analysis. These isolates belonged to different clones: ST7, ST480, and ST585. In these three isolates, the optrA gene was located on plasmids, associated with IS1216 in different arrays. In one isolate, the optrA plasmid coexists with a second plasmid, which carried multiple resistance genes for different classes of antibiotics. Detection of optrA-positive E. faecalis isolates in the community is a matter of concern. The spread of these bacteria into hospital settings, particularly in those, such as the HEB, where vancomycin-resistant enterococci are endemic, should be avoided, to preserve the efficacy of the last-resort oxazolidinones.


Assuntos
Enterococcus faecium , Infecções por Bactérias Gram-Positivas , Oxazolidinonas , Antibacterianos/farmacologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Farmacorresistência Bacteriana/genética , Enterococcus , Enterococcus faecalis , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Infecções por Bactérias Gram-Positivas/epidemiologia , Infecções por Bactérias Gram-Positivas/microbiologia , Humanos , Linezolida/farmacologia , Testes de Sensibilidade Microbiana , Oxazolidinonas/farmacologia
7.
J Infect Chemother ; 28(9): 1235-1241, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35718656

RESUMO

INTRODUCTION: The results from the phase 3 study that evaluated the efficacy and safety of tedizolid phosphate, an oxazolidinone drug, for the treatment of gram-positive ventilated hospital-acquired bacterial pneumonia (vHABP)/ventilator-associated bacterial pneumonia (VABP) compared with linezolid (VITAL study), have been previously reported. We conducted a subgroup analysis to report the data obtained from Japanese patients enrolled in this study. METHODS: Patients aged ≥18 years with vHABP/VABP likely to be caused by gram-positive cocci were randomized 1:1 to tedizolid phosphate 200 mg once daily for 7 days or linezolid 600 mg twice daily for 10 days. In both treatment groups, patients with concurrent gram-positive bacteremia were treated for 14 days. Primary efficacy endpoints were day 28 all-cause mortality (ACM) and investigator-assessed clinical response at test-of-cure (TOC) in the intention-to-treat population. Safety outcomes included assessment of treatment-emergent adverse events. RESULTS: Fifty-three Japanese patients were randomized at received study drug (tedizolid, n = 28; linezolid, n = 25). Demographics and characteristics were generally similar between treatment groups. Rates of day 28 ACM were 10.7% and 20.0% with tedizolid and linezolid, respectively (difference, 9.3%; 95% CI, -10.1 to 28.7). Rates of investigator-assessed clinical cure at TOC were 78.6% and 72.0% with tedizolid and linezolid, respectively (difference, 6.6%; 95% CI, -16.7 to 29.8). Tedizolid phosphate was generally well tolerated and no new safety concerns were observed in the Japanese subgroup. CONCLUSION: The results from this subgroup analysis suggest generally favorable efficacy and safety of tedizolid in adult Japanese patients with vHABP/VABP. (ClinicalTrials.gov identifier: NCT02019420).


Assuntos
Oxazolidinonas , Pneumonia Bacteriana , Pneumonia Associada à Ventilação Mecânica , Dermatopatias Bacterianas , Adolescente , Adulto , Antibacterianos/efeitos adversos , Bactérias , Método Duplo-Cego , Hospitais , Humanos , Japão , Linezolida/efeitos adversos , Organofosfatos , Oxazolidinonas/efeitos adversos , Pneumonia Bacteriana/tratamento farmacológico , Pneumonia Associada à Ventilação Mecânica/tratamento farmacológico , Dermatopatias Bacterianas/tratamento farmacológico , Tetrazóis , Ventiladores Mecânicos
8.
Food Funct ; 13(13): 7260-7273, 2022 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-35723416

RESUMO

As living standards improve, obesity has become an increasingly serious health problem. Natural extracts from a wide range of sources are non-toxic and have significant potential as drugs for the prevention and treatment of obesity. We assessed 243 natural small molecules in a HepG2 fat accumulation model and found that epigoitrin (EP) from Radix isatidis reduced intracellular fat deposition, increased short-chain acyl CoA dehydrogenase (SCAD) activity, promoted glucose uptake and glycogen storage, increased ATP production and reduced glutathione (GSH) content, reduced reactive oxygen species (ROS), and enhanced superoxide dismutase (SOD) activity. In a murine high-fat diet model, the addition of EP to the high-fat diet significantly reduced fat deposition, increased glucose tolerance, improved insulin sensitivity, and increased energy expenditure. In conclusion, EP alleviated obesity caused by a high-fat diet and improved disorders of lipid and glucose metabolism.


Assuntos
Transtornos do Metabolismo de Glucose , Resistência à Insulina , Animais , Dieta Hiperlipídica/efeitos adversos , Transtornos do Metabolismo de Glucose/tratamento farmacológico , Transtornos do Metabolismo de Glucose/etiologia , Metabolismo dos Lipídeos , Lipídeos , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Oxazolidinonas
9.
Bioorg Chem ; 126: 105869, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35598571

RESUMO

The quest for new antifungal and antitubercular drugs is a need of the hour because of morbid co-pathogenesis and an increase in immunocompromised patients. One of the ways forward is to explore and repurpose the established pharmacophores for the desired application. Oxazolidinones are well-known antibacterial agents, with few investigations reported to exploit their antifungal properties. Herein, we report the design and synthesis of a series of linezolid-based oxazolidinones as potent anticandidiasis and antitubercular agents. Studies revealed that two of the novel oxazolidinones 2 and 3a exhibited excellent anticandidiasis activity against different Candida fungus strains, superior to standard drugs. Mechanistic and docking studies revealed that oxazolidinones were better inhibitors of the ergosterol biosynthesis pathway than the controls used. In addition, the oxazolidinones 2 and 3a also exhibited prominent inhibitory activity against M. tuberculosis H37Rv with MIC values of 1 and 2 µg/ml, respectively. Computational studies demonstrated the binding of the compounds to the transcriptional regulatory repressor protein, which was reinforced by the molecular dynamics simulations. The pharmacophore modeling experiments validated the molecular docking results in both the target proteins.


Assuntos
Mycobacterium tuberculosis , Oxazolidinonas , Antibacterianos/farmacologia , Antifúngicos/farmacologia , Antituberculosos/farmacologia , Humanos , Linezolida/farmacologia , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Oxazolidinonas/química , Oxazolidinonas/farmacologia
10.
Diagn Microbiol Infect Dis ; 103(3): 115714, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35596983

RESUMO

The effects of tedizolid (TZD) against multidrug-resistant Mycobacterium tuberculosis isolates were investigated. This is possibly the first study to evaluate the MIC of TZD against Japanese Mycobacterium tuberculosis isolates. As TZD had a significantly lower MIC than LZD (P < 0.01), it was suggested to be a better, non-toxic alternative to LZD.


Assuntos
Mycobacterium tuberculosis , Tuberculose Resistente a Múltiplos Medicamentos , Antibacterianos/farmacologia , Genômica , Humanos , Linezolida/farmacologia , Testes de Sensibilidade Microbiana , Oxazolidinonas , Tetrazóis , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia
11.
Luminescence ; 37(7): 1174-1183, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35506182

RESUMO

Sensitive and selective spectrophotometric and spectrofluorimetric methods have been developed for the estimation of two anti-migraine drugs, namely sumatriptan succinate (SUM) and zolmitriptan (ZOL). These methods depend on producing a yellow-coloured product after the reaction of the two drugs with 7-chloro-4-nitrobenz-2-oxa-1,3-diazole (NBD-Cl). The reaction products exhibited maximum absorbance at 481 nm in borate buffer of pH 9 and fluorescence emission peak at 540 nm after excitation at 470 nm for the two drugs. The linear ranges were 5-60 µg/ml for SUM and 5-50 µg/ml for ZOL in the spectrophotometric method (Method I), whereas this was 0.4-4 µg/ml for SUM and 0.5-5 µg/ml for ZOL in the spectrofluorimetric method (Method II). The method validity was assessed according to International Council for Harmonisation (ICH) guidelines. Statistical analysis of the results obtained from the proposed and comparison methods confirmed that the proposed methods were highly accurate and precise. The suggested methods could be used for the determination of the mentioned drugs in both pure form and in tablets.


Assuntos
Sumatriptana , Triptaminas , Concentração de Íons de Hidrogênio , Oxazolidinonas , Espectrometria de Fluorescência/métodos , Comprimidos
12.
Spectrochim Acta A Mol Biomol Spectrosc ; 279: 121408, 2022 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-35617839

RESUMO

Polyvinyl pyrrolidone (PVP), playing roles as a templating agent, can be applied to prepare blue-emitting copper nanoclusters (Cu NCs@PVP) on the basis of a rapid chemical reduction synthesis method. The Cu NCs@PVP displayed a blue emission wavelength at 430 nm and the corresponding quantum yield (QY) could reach 10.4%. Subsequently, the as-synthesized Cu NCs@PVP were used for the trace analysis of furaltadone based on the inner filter effect (IFE) between Cu NCs@PVP and furaltadone, which caused the fluorescence to be effectively quenched. Additionally, this proposed determination platform based on the Cu NCs@PVP for furaltadone sensing possessed an excellent linear range from 0.5 to 100 µM with a lower detection limit of 0.045 µM (S/N = 3). Meanwhile, the Cu NCs@PVP also could be applied for the sensing of temperature. Furthermore, the practicability of the sensing platform has been successfully verified by measuring furaltadone in real samples, affirming its potential to increase fields for the determination of furaltadone.


Assuntos
Nitrofuranos , Oxazolidinonas , Cobre , Corantes Fluorescentes , Espectrometria de Fluorescência/métodos , Temperatura
13.
Clin Exp Pharmacol Physiol ; 49(9): 950-958, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35637550

RESUMO

Thyrotropin-releasing hormone (TRH) and the TRH mimetic taltirelin have been used in Japan for the treatment of spinocerebellar degeneration (SCD), a type of progressive ataxia. A TRH mimetic, rovatirelin, ameliorates ataxia symptoms in the rolling mouse Nagoya, a hereditary SCD model. The aim of this study was to verify the effects of oral administration of rovatirelin on a cytosine arabinoside (Ara-C)-induced ataxia rat model, a sporadic SCD model characterized by gait abnormalities and falls because of cerebellar atrophy and investigate the central nervous system mechanism associated with rovatirelin-mediated amelioration of motor dysfunction in these rats. Rovatirelin at ≥3 mg/kg significantly decreased the fall index, which is a primary endpoint of improved motor function calculated by dividing the number of falls by the locomotor activity, in both male and female rats with Ara-C-induced ataxia. Furthermore, rovatirelin caused a significant increase in locomotor activity in a dose-dependent manner. Taltirelin at ≥30 mg/kg ameliorated motor dysfunction in ataxic rats. Moreover, rovatirelin significantly increased acetylcholine (ACh) levels in the medial prefrontal cortex (mPFC) and dopamine (DA) levels in the nucleus accumbens (NAc) at ≥3 mg/kg and significantly increased DA levels in the dorsal striatum at ≥10 mg/kg in normal rats. In conclusion, oral administration of rovatirelin ameliorates motor dysfunction in rats with Ara-C-induced ataxia, owing to its ACh-increasing effects in the mPFC and DA-increasing effects in the dorsal striatum and NAc. Furthermore, the effects of rovatirelin were more potent than those of taltirelin.


Assuntos
Dopamina , Degenerações Espinocerebelares , Acetilcolina , Animais , Ataxia/induzido quimicamente , Citarabina/efeitos adversos , Feminino , Masculino , Camundongos , Oxazolidinonas , Pirrolidinas , Ratos , Transmissão Sináptica , Hormônio Liberador de Tireotropina/efeitos adversos
14.
Antimicrob Agents Chemother ; 66(6): e0243021, 2022 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-35575579

RESUMO

This study aimed to build a population pharmacokinetic (PopPK) model for contezolid tablet (MRX-I) in healthy subjects and adults with complicated skin and soft-tissue infections (cSSTIs) to further evaluate the efficacy and safety of contezolid and recommend the optimal dosing regimen based on pharmacokinetic/pharmacodynamic (PK/PD) analysis. PopPK analysis was performed using a nonlinear mixed-effects model (NONMEM) to examine the effects of age, body weight, sex, liver and renal functions, albumin, food, dosage strength, and subject type on the PK parameters of contezolid. PK/PD analysis was combined with the MIC of contezolid, clinical/microbiological efficacy, and nonclinical study data. Adverse events (AEs) and study drug-related AEs reported were summarized to examine the relationship between contezolid exposure level and safety measures. A two-compartment model was built. An exponential model was used to describe the interindividual variation. A proportional model was used to describe the intraindividual variation of PK parameters. Good clinical and microbiological efficacy are expected for the infections caused by S. aureus when contezolid is administered at 600 mg or 800 mg every 12 h (q12h). The area under the concentration-time curve from 0 to 24 h at steady state and maximum concentration of drug in serum at steady state of contezolid did not show significant association with the incidence of any AE. The dosing regimen of contezolid at 800 mg q12h administered postprandially for 7 to 14 days is expected to achieve satisfactory clinical and microbiological efficacy in cSSTIs, which is slightly better than that of 600 mg contezolid. This administration has been added to the prescribing information of contezolid tablets.


Assuntos
Farmacologia Clínica , Infecções dos Tecidos Moles , Adulto , Antibacterianos/farmacologia , China , Humanos , Oxazolidinonas , Piridonas , Infecções dos Tecidos Moles/tratamento farmacológico , Staphylococcus aureus
15.
J Antimicrob Chemother ; 77(8): 2125-2129, 2022 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-35640656

RESUMO

OBJECTIVES: To characterize the oxazolidinone resistance gene poxtA in a Lactobacillus salivarius isolate of pig origin. METHODS: L. salivarius isolate BNS11 was investigated for the presence of mobile oxazolidinone resistance genes by PCR. Antimicrobial susceptibility testing was performed by broth microdilution. Transfer experiments were conducted to assess horizontal transferability of the gene poxtA. WGS was carried out using a combination of Oxford Nanopore MinION/Illumina HiSeq platforms. The presence of translocatable units (TUs) carrying resistance genes was studied by PCR assays and subsequent sequence analysis. RESULTS: L. salivarius isolate BNS11 was positive for poxtA. WGS showed that it harboured two gene copies each of the poxtA and the fexB genes, which were located on the broad-host-range Inc18 plasmid pBNS11-37kb and in the chromosomal DNA, respectively. The plasmid-borne poxtA gene together with the genes fexB, vat(E) and erm(C) were located in an MDR region on plasmid pBNS11-37kb. Analysis of the genetic context showed that an approx. 11 kb poxtA-fexB fragment was integrated into the chromosomal DNA and two novel IS elements ISLasa1 and ISLasa2 were identified in this inserted fragment. PCR assays revealed that five different IS1216E-based TUs carrying the resistance genes poxtA, fexB, vat(E) or erm(C) were formed. CONCLUSIONS: To the best of our knowledge, this is the first report of the transferable oxazolidinone resistance gene poxtA in the genus Lactobacillus. In addition, the presence of IS1216E-based TUs will contribute to the persistence and accelerate the dissemination of resistance genes, including poxtA.


Assuntos
Lactobacillus salivarius , Oxazolidinonas , Animais , Antibacterianos/farmacologia , Farmacorresistência Bacteriana/genética , Genes Bacterianos , Lactobacillus salivarius/genética , Testes de Sensibilidade Microbiana , Oxazolidinonas/farmacologia , Plasmídeos/genética , Suínos , Resistência a Tetraciclina/genética
16.
Chirality ; 34(8): 1044-1052, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35577389

RESUMO

This paper reports the separation of two chiral antibacterial agents namely, linezolid and tedizolid using a validated high-performance liquid chromatographic method. In the current work, glycopeptide-based chiral column, CHIROBIOTIC® V2 (5-µm particle size, L × I.D. 25 cm × 4.6 mm) was employed with a mobile phase containing methanol and 0.15% aq. trifluoracetic acid (75:25%, v/v) in isocratic elution approach at flow rate of 1 ml min-1 . The separation condition was customized (in terms of resolution values and retention times) was carried out by changing the content of the mobile phase, column temperature, flow rate, and so on. Results showed that the chromatographic separation was achieved within 15 min and average resolution values were 4.6 and 4.8 for tedizolid and linezolid, respectively. The detection limit values were 14.85 and 14.16 ng ml-1 , respectively, for tedizolid enantiomers. Further, validation of separation parameters was performed by considering the international conference on harmonization guidelines, and ultimately, the mechanism of chiral recognition was also established.


Assuntos
Oxazolidinonas , Cromatografia Líquida de Alta Pressão/métodos , Linezolida , Estereoisomerismo , Tetrazóis
17.
Biol Pharm Bull ; 45(4): 421-428, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35370266

RESUMO

It is important to select appropriate antibiotics for infection control. Linezolid and tedizolid are newly developed and synthesized oxazolidinone antibacterial agents. It has been pointed out that there is a relationship between a high plasma concentration of the target drug and incidence of adverse effects, although it has been reported that neither linezolid nor tedizolid requires dose adjustment according to renal function. Due to the high incidence of adverse effects, both are often switched. Precise plasma concentration control by therapeutic drug monitoring (TDM) is desirable for reducing the adverse effects of both drugs and obtaining a better therapeutic effect. In this study, we aimed to establish a method for simultaneous quantification of linezolid and tedizolid in human plasma using LC coupled with tandem mass spectrometry. Sample preparation was performed by a simple operation with acetonitrile. Linezolid and tedizolid were separated by an octadecylsilyl column using a gradient elution of acetonitrile in aqueous 0.1% formic acid solution and were detected in the positive ion electrospray mode with multiple reaction monitoring. Quantification of linezolid and tedizolid ranged from 0.5 to 50 and 0.5 to 20 µg/mL, respectively. The intra-day and inter-day precision and accuracy of data were assessed and found to be acceptable. The developed method was successfully applied to measurement of the concentrations of linezolid and tedizolid. This simple method, which can simultaneously quantify both drug concentrations for daily TDM, could contribute to safer treatment of patients.


Assuntos
Oxazolidinonas , Espectrometria de Massas em Tandem , Cromatografia Líquida/métodos , Humanos , Linezolida , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos , Tetrazóis
18.
Chirality ; 34(7): 915-924, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35488466

RESUMO

Although the wide variety of heterocyclic compounds is common knowledge, chiral 2-oxazolidinones are recognized as some of the most important heterocycles in medicinal chemistry. Many important pharmaceutical molecules have been constructed based on the chiral 2-oxazolidinone backbone. Therefore, the development of even more efficient catalytic methods for the synthesis of chiral 2-oxazolidinones remains a very important pursuit in the field of synthetic organic chemistry. This review summarizes the coupling reactions of epoxides and isocyanates for the preparation of 2-oxazolidinones. Both metal catalysts and organocatalysts promote these reactions. Optically pure 2-oxazolidinones are prepared from optically pure epoxide substrates via these catalytic methods. A synthetic example of a commercially available pharmaceutical compound utilizing this method is also introduced.


Assuntos
Compostos Heterocíclicos , Oxazolidinonas , Catálise , Compostos de Epóxi/química , Compostos Heterocíclicos/química , Preparações Farmacêuticas , Estereoisomerismo
19.
Nat Commun ; 13(1): 1860, 2022 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-35387982

RESUMO

PoxtA and OptrA are ATP binding cassette (ABC) proteins of the F subtype (ABCF). They confer resistance to oxazolidinone and phenicol antibiotics, such as linezolid and chloramphenicol, which stall translating ribosomes when certain amino acids are present at a defined position in the nascent polypeptide chain. These proteins are often encoded on mobile genetic elements, facilitating their rapid spread amongst Gram-positive bacteria, and are thought to confer resistance by binding to the ribosome and dislodging the bound antibiotic. However, the mechanistic basis of this resistance remains unclear. Here we refine the PoxtA spectrum of action, demonstrate alleviation of linezolid-induced context-dependent translational stalling, and present cryo-electron microscopy structures of PoxtA in complex with the Enterococcus faecalis 70S ribosome. PoxtA perturbs the CCA-end of the P-site tRNA, causing it to shift by ∼4 Šout of the ribosome, corresponding to a register shift of approximately one amino acid for an attached nascent polypeptide chain. We postulate that the perturbation of the P-site tRNA by PoxtA thereby alters the conformation of the attached nascent chain to disrupt the drug binding site.


Assuntos
Oxazolidinonas , Antibacterianos/farmacologia , Microscopia Crioeletrônica , Farmacorresistência Bacteriana/genética , Enterococcus faecalis/genética , Linezolida/farmacologia , Oxazolidinonas/farmacologia , RNA de Transferência/genética
20.
Drug Discov Ther ; 16(2): 99-101, 2022 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-35418550

RESUMO

Tuberculosis has become a great global public health threat. Compared with drug-susceptible tuberculosis (TB), the treatment regimens for multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) involve more severe adverse events and poorer treatment outcomes. Linezolid (LZD) is the first oxazolidinones used for TB. Thanks to its potent activity against Mycobacterium tuberculosis, LZD has become one of the key agents in the regimens against MDR/XDR-TB. However, this drug may cause intolerability and other adverse events. Contezolid, another novel oxazolidinone, can also inhibit M. tuberculosis, still with fewer adverse effects compared with LZD. This paper is to prospect the potentials of contezolid in the treatment of MDR/XDR-TB, with focus on its efficacy and possible adverse effects.


Assuntos
Tuberculose Extensivamente Resistente a Medicamentos , Mycobacterium tuberculosis , Oxazolidinonas , Tuberculose Resistente a Múltiplos Medicamentos , Antituberculosos/efeitos adversos , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Tuberculose Extensivamente Resistente a Medicamentos/microbiologia , Humanos , Linezolida/efeitos adversos , Testes de Sensibilidade Microbiana , Oxazolidinonas/efeitos adversos , Piridonas , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia
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