Synthesis and antibacterial evaluation of novel oxazolidinone derivatives containing a piperidinyl moiety

In this article, a series of novel oxazolidinone derivatives containing a piperidinyl moiety was designed and synthesized. Their antibacterial activities were measured against S. aureus, MRSA, MSSA, LREF and VRE by MIC assay. Most of them exhibited potent activity against Gram-positive pathogens comparable to linezolid. Among them, compound 9h exhibited comparable activity with linezolid against human MAO-A for safety evaluation and showed moderate metabolism in human liver microsome. The most promising compound 9h, which showed remarkable antibacterial activity against S. aureus, MRSA, MSSA, LREF and VRE pathogens with MIC value of 0.25–1 μg/mL, was an interesting candidate for further investigation.     

乌司他丁联合利奈唑胺对重症肺炎患者血清PCT、CRP、TNF-α及白细胞计数的影响

目的:探讨乌司他丁联合利奈唑胺对重症肺炎患者血清降钙素原(PCT)、C-反应蛋白(CRP)、肿瘤坏死因子-α(TNF-α)及白细胞计数的影响。方法:选择2014年2月-2018年2月在我院住院诊治的重症肺炎患者128例,根据治疗方法的不同分为观察组68例与对照组60例,对照组给予利奈唑胺治疗,观察组在对照组治疗的基础上给予乌司他丁治疗,两组都治疗观察2周,检测和比较两组治疗后临床疗效,治疗前后1秒钟用力呼气量占用力肺活量比值(FEV1/FVC)、血清PCT、CRP、TNF-α水平及白细胞计数的变化情况。结果:观察组与对照组的治疗总有效率分别为94.1%和76.7%,观察组的总有效率显著高于对照组(P0.05)。观察组与对照组治疗后的FEV1/FVC值、白细胞计数均显著高于治疗前(P0.05),且观察组以上指标明显高于对照组(P0.05)。观察组与对照组治疗后的血清PCT、CRP、TNF-α水平都显著低于治疗前(P0.05),且观察组以上指标均显著低于对照组(P0.05)。结论:乌司他丁联合利奈唑胺治疗重症肺炎患者能显著提高临床疗效,改善患者肺功能,可能与其降低血清PCT、CRP、TNF-α水平,提高白细胞计数有关。     

利奈唑胺与万古霉素对MRSA肺炎患者血清CRP

目的：研究利奈唑胺与万古霉素治疗耐甲氧西林金黄色葡萄球菌（Methicillin-resistant , MRSA）肺炎的 临床疗效。方法：选取2010 年10 月至2013 年10 月在我院就诊的60例MRSA肺炎患者的临床资料进行分析,根据治疗方法的 不同,将所选病例分为利奈唑胺组和万古霉素组。统计并分析两组患者的临床疗效、细菌学疗效以及炎症因子水平的变化情况, 并对两种药物的安全性进行评价。结果：利奈唑胺组治疗有效率为83.33 %,致病菌清除率为86.67 %,不良反应发生率为9.52 %; 万古霉素组治疗有效率为86.67 %,致病菌清除率为84.33 %,不良反应发生率为16.00 %;但两组比较差异无统计学意义（P>0. 05）。两组患者治疗后血清中CRP、TNF-alpha 水平较治疗前明显降低,利奈唑胺组下降幅度明显高于万古霉素组,差异具有统计学意 义（P<0.05）。结论：两种药物治疗老年MRSA 肺炎的疗效差异性不大,但利奈唑胺整体优于万古霉素。     

耐利奈唑胺粪肠球菌感染的危险因素分析

分析深圳市南山区人民医院粪肠球菌感染患者的临床资料,探讨引起感染的危险因素,为防治耐利奈唑胺粪肠球菌感染提供临床参考。选取2010年1月-2015年9月在深圳市南山区人民医院住院的165例粪肠球菌感染患者,根据药敏结果分为利奈唑胺敏感组(103例)和利奈唑胺中介/耐药组(62例)。165例粪肠球菌主要来源于中段尿培养,占53.94%,其次为伤口分泌物培养(21.82%)、血培养(6.06%);科室分布以泌尿外科和肝胆外科为主,分别占35.76%和9.70%。单因素分析显示,碳青霉烯类抗生素暴露、留置尿管与感染相关。Logistic回归分析进一步明确碳青霉烯类抗生素暴露、留置尿管为耐利奈唑胺粪肠球菌感染的危险因素,提示应严格掌握碳青霉烯类抗生素的适应证,加强医院内感染的控制管理。     

Elucidation of the RNA target of linezolid by using a linezolid-neomycin B heteroconjugate and genomic SELEX

A covalently modified heteroconjugate between linezolid and neomycin B leads to an enhanced and more specific binding affinity to hairpin RNA targets in comparison to neomycin B itself. This heteroconjugate was used as a lure to select linezolid-specific hairpin RNA from an Escherichia coli genome RNA. The selected RNA obtained after eight cycles not only has typical stem–loop structures but also includes known sequences of the linezolid binding site. The results of RNA footprinting show that the binding site of the heteroconjugate encompasses both stem and loop regions, suggesting that the possible binding site for linezolid is in the terminal loop. In addition, findings from application of a surface plasmon resonance assay clearly demonstrate that linezolid binds to selected hairpin RNA in a highly specific manner with a low millimolar affinity. The results suggest that heteroconjugates might represent a generally useful approach in studies aimed at uncovering loop-specific RNA binding ligands that would be otherwise difficult to identify owing to their weak affinities.     

Evaluation of anti-depressant-like activity of linezolid, an oxazolidinone class derivative - an investigation using behavioral tests battery of depression

Linezolid, an oxazolidinone class derivative is a reversible and nonselective inhibitor of monoamine oxidase (MAO), predominantly for MAO-A type. MAO-A is a key enzyme regulating the catabolism of catecholamine neurotransmitters in the brain. It is well known that the catecholaminergic neuronal systems are associated with depression and inhibition of MAO-A level in the brain could be used to treat depression. Hence, the objective of this study was to evaluate the anti-depressant-like effect of linezolid, a MAO-A inhibitor in the animal models of depression. In the present study, linezolid (10 & 20 mg/kg, i.p.), exhibited anti-depressant-like effects in forced swim test (FST) and tail suspension test (TST) in mice without influencing the baseline locomotion. Moreover, linezolid (10 & 20 mg/kg, i.p.), potentiated the 5-hydroxytryptophan (5-HTP)-induced head twitch responses in mice and antagonized the reserpine-induced hypothermia in rats. In conclusion, the behavioral investigation revealed the anti-depressant-like effect of linezolid in rodent’s behavioral model.     

New potent antibacterials against Gram-positive multiresistant pathogens: Effects of side chain modification and chirality in linezolid-like 1,2,4-oxadiazoles

The effects of side chain modification and chirality in linezolid-like 1,2,4-oxadiazoles have been studied to design new potent antibacterials against Gram-positive multidrug-resistant pathogens. The adopted strategy involved a molecular modelling approach, the synthesis and biological evaluation of new designed compounds, enantiomers separation and absolute configuration assignment. Experimental determination of the antibacterial activity of the designed (S)-1-((3-(4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-oxazolidin-2-one-5-yl)methyl)-3-methylthiourea and (S)-1-((3-(3-fluoro-4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-oxazolidin-2-one-5-yl)methyl)-3-methylthiourea against multidrug resistant linezolid bacterial strains was higher than that of linezolid.     

Synthesis and biological evaluation of novel benzoxazinyl-oxazolidinones as potential antibacterial agents

A number of benzoxazinyl-oxazolidinones bearing 3-trizolylmethyl or 3-carboxamide side chain were designed and synthesized with the aim to develop antibacterial agents with improved properties. In vitro antibacterial activities of these novel compounds were evaluated against a panel of resistant and susceptible Gram-positive bacteria. Most analogues bearing 3-trizolylmethyl showed good to moderate antibacterial activities. Compound 12a exhibited a fourfold increase in activity compared with linezolid against all the tested strains, which was identified to be a promising antibacterial agent for further evaluation.     

Incorporation of a chiral gem-disubstituted nitrogen heterocycle yields an oxazolidinone antibiotic with reduced mitochondrial toxicity

gem-Disubstituted N-heterocycles are rarely found in drugs, despite their potential to improve the drug-like properties of small molecule pharmaceuticals. Linezolid, a morpholine heterocycle-containing oxazolidinone antibiotic, exhibits significant side effects associated with human mitochondrial protein synthesis inhibition. We synthesized a gem-disubstituted linezolid analogue that when compared to linezolid, maintains comparable (albeit slightly diminished) activity against bacteria, comparable in vitro physicochemical properties, and a decrease in undesired mitochondrial protein synthesis (MPS) inhibition. This research contributes to the structure-activity-relationship data surrounding oxazolidinone MPS inhibition, and may inspire investigations into the utility of gem-disubstituted N-heterocycles in medicinal chemistry.