CN116350613B - Bms-303141用于制备抗革兰氏阳性细菌感染药物中的应用 - Google Patents
Bms-303141用于制备抗革兰氏阳性细菌感染药物中的应用 Download PDFInfo
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- CN116350613B CN116350613B CN202310071884.9A CN202310071884A CN116350613B CN 116350613 B CN116350613 B CN 116350613B CN 202310071884 A CN202310071884 A CN 202310071884A CN 116350613 B CN116350613 B CN 116350613B
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- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
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Abstract
本发明提供了BMS‑303141用于制备抗革兰氏阳性细菌感染药物中的应用,所述BMS‑303141,CAS编号为943962‑47‑8。本发明的技术方案公开了BMS‑303141的医药新用途,BMS‑303141对革兰氏阳性细菌具有强效抑制作用,可以抑制如金黄色葡萄球菌、粪肠球菌、表皮葡萄球菌等细菌的生长和生物被膜的形成,而且表现出一定的杀革兰氏阳性细菌中金黄色葡萄球菌和粪肠球菌的活性。
Description
技术领域
本发明属于医药技术领域,尤其涉及BMS-303141用于制备抗革兰氏阳性细菌感染药物中的应用。
背景技术
金黄色葡萄球菌、粪肠球菌和屎肠球菌等革兰氏阳性菌是社区感染和院内感染的常见的病原菌。其中金黄色葡萄球菌能产生血浆凝固酶,又称为血浆凝固酶阳性葡萄球菌,也是致病性最强的葡萄球菌之一。据2020年全国耐药监测报告显示,革兰阳性菌分离率排在首位的是:金葡萄(占革兰阳性菌32.6%),紧随其后的是屎肠球菌、粪肠球菌、表葡菌和肺炎链球菌等。金黄色葡萄球菌作为临床分离常见的病原菌,可引起多种临床感染,从轻微的皮肤感染,骨关节炎、感染性心内膜炎,假体装置感染,甚至到严重致命的组织感染和败血症,威胁着大众的健康。临床上根据金黄色葡萄球菌对甲氧西林的敏感性分为甲氧西林敏感金黄色葡萄球菌(MSSA)以及耐甲氧西林金黄色葡萄球菌(MSSA)两大类。2015年版《多重耐药菌医院感染预防与控制中国专家共识》提到,MRSA感染宜选的药物有糖肽类抗生素,如万古霉素、去甲万古霉素、替考拉宁,备选的药物还有达托霉素、利奈唑胺和替加环素等。尽管目前抗革兰氏阳性菌可选的抗菌药物较多,但是近年来,由于抗生素的广泛应用以及新型抗菌药物的研发过程漫长艰难,耐药菌株日益增多,尤其是MRSA已成为感染的重要致病菌之一。据报道,美国MRSA造成的死亡率仍然是任何抗生素耐药性病原体中最高的,2018年约为20,000人,2020年我国MRSA的全国平均检出率为29.4%。虽然抗生素可通过抑制/杀死细菌控制感染,但是,也导致获得突变的耐药菌株存活并传播,耐药细菌传播速度远超过了新抗菌药物的研发速度,一旦细菌对顶级抗生素产生耐药性,会给临床上治疗感染带来了更严峻挑战。传统的抗生素的作用是杀菌和抑菌,主要机制是通过影响细胞壁合成、阻止细菌DNA复制、抑制生长所需的蛋白质等控制细菌生长。所以开发新靶点、具有广谱抗菌活性的抗菌药物可为临床治疗上提供更多的选择,也有利于抗菌药物的进一步开发。
除特异性抗生素耐药性外,生物膜形成的非特异性抗生素耐药性在许多与生物膜相关的金黄色葡萄球菌感染中也发挥作用。生物被膜形成是影响革兰阳性细菌抗感染疗效的难点问题之一。细菌生物被膜是一种具有独特三维立体结构的细菌聚集群,其由细菌及细菌分泌的多糖、纤维蛋白、脂蛋白等构成,一旦生物被膜形成,被膜里的细菌的生长代谢方式明显不同于浮游菌,被膜能够有效地阻止抗菌药物的扩散与渗透,从而使得细菌逃避抗菌药物的杀伤。此外,生物被膜内含大量持留菌,持留菌是具有耐药表型的小亚群,表现为临时的休眠或低代谢状态,也可耐受抗菌药物压力。细菌耐药、持留菌和生物被膜形成均可导致革兰阳性细菌(包括金黄色葡萄球菌、粪肠球菌、屎肠球菌等)感染持续时间延长,是感染治疗失败的重要因素,最终导致患者死亡风险升高。
当前临床使用的一线抗生素往往难以具备杀灭持留菌活性和清除细菌生物被膜双重活性,因此针对革兰阳性细菌开发新型抗菌药物,既能克服细菌耐药,又能强效杀灭持留菌和抑制生物被膜形成成为研究重难点。
发明内容
针对以上技术问题,本发明公开了BMS-303141用于制备抗革兰氏阳性细菌感染药物中的应用,BMS-303141具有高效的抗革兰氏阳性细菌生长和抗生物被膜的活性,并且可能靶向某些关键蛋白发挥抗菌活性。
对此,本发明采用的技术方案为:
BMS-303141用于制备抗革兰氏阳性细菌感染药物中的应用,所述BMS-303141,CAS编号为943962-47-8;所述BMS-303141具有抑制革兰氏阳性菌的生长和生物被膜形成的作用。
其中,所述BMS-303141的结构式如式(1)所示:
BMS-303141,其英文全称为:
3,5-dichloro-2-hydroxy-N-(4-methoxy[1,1'-biphenyl]-3-yl)-benzenesulfonamide,它是一种高效性和可渗透细胞的ATP-柠檬酸裂解酶(ATP-citratelyase,ACL)抑制剂,IC50值为0.13μM。研究发现在HepG 2的细胞实验中,在没有产生细胞毒性的情况下,BMS-303141抑制总脂合成的IC50为8μM。在小鼠的药代动力学模型中,BMS-303141的口服生物利用度为55%,但半衰期相对较短,为2.1h;因此在James J.Li研究中采用了将BMS-303141掺入食物中的方法,在高脂肪喂养的小鼠中长期口服10mg/kg和100mg/kg BMS-303141降低了血浆胆固醇、甘油三酯和葡萄糖,并抑制了体重增加。研究还发现在LPS诱导的腹膜炎模型中,BMS-303141治疗组小鼠,腹膜和血清中IL-6和IL-12p70的表达水平下降。这表明BMS-303141能够改变局部和全身的炎症谱系。用BMS-303141抑制ACL,可消除CpG处理的巨噬细胞增强的肿瘤细胞吞噬功能。但是,至今未见BMS-303141化合物在抗菌方面上的报道。
经过大量的实验研究,化合物BMS-303141对多株金黄色葡萄球菌(MIC:12.5μM)、表葡菌(MIC:3.125-12.5μM)和粪肠球菌(MIC:12.5-25μM)均具有较好的抑菌活性(表1);BMS-303141在1×MIC能够完全抑制金黄色葡萄球菌和粪肠球菌的生长,甚至有的在1/2×MIC浓度下也可以抑制金黄色葡萄球菌和粪肠球菌的生长,并且能够显著抑制生物被膜的形成。同时与公认的常用抗生素对比,BMS-303141对金黄色葡萄球菌及粪肠球菌具有较好的杀菌效果。
作为本发明的进一步改进,所述革兰氏阳性细菌为金黄色葡萄球菌、粪肠球菌、屎肠球菌、表皮葡萄球菌或肺炎链球菌中的至少一种。
作为本发明的进一步改进,所述BMS-303141在处理体系中的浓度为不小于3.125μM(1.33μg/ml)。
作为本发明的进一步改进,所述药物为药物组合物或制剂。进一步的,所述药物为注射剂、片剂、丸剂、胶囊、悬浮剂、颗粒剂、喷剂或乳剂。
本发明还公开了BMS-3031413用于制备抑制革兰氏阳性菌的涂料中的应用,所述涂料用于医疗器械的表面,所述BMS-3031413的CAS编号为943962-47-8,结构式如式(1)所示;所述BMS-3031413具有抑制革兰氏阳性菌的生长和生物被膜形成的作用。
作为本发明的进一步改进,所述涂料中,所述BMS-3031413的浓度为不小于3.125μM。
本发明还公开了BMS-303141用于制备抗革兰氏阳性菌抗菌剂的应用,所述BMS-303141的CAS编号为943962-47-8,,结构式如式(1)所示;所述BMS-303141具有抑制革兰氏阳性菌的生长和生物被膜形成的作用。
与现有技术相比,本发明的有益效果为:
本发明的技术方案公开了BMS-303141的医药新用途,BMS-303141对革兰氏阳性细菌具有强效抑制作用,可以抑制如金黄色葡萄球菌、粪肠球菌、表皮葡萄球菌等细菌的生长和生物被膜的形成,而且表现出一定的杀革兰氏阳性细菌中金黄色葡萄球菌和粪肠球菌的活性。其中化合物BMS-303141对多株金黄色葡萄球菌(MIC:12.5μM)、表葡菌(MIC:3.125-12.5μM)和粪肠球菌(MIC:12.5-25μM)均具有较好的抑菌活性;BMS-303141在1×MIC能够完全抑制金黄色葡萄球菌和粪肠球菌的生长,甚至有的在1/2×MIC浓度下也可以抑制金黄色葡萄球菌和粪肠球菌的生长,并且能够显著抑制生物被膜的形成;同时,与公认的抗生素万古霉素和利奈唑胺对比,BMS-303141对金黄色葡萄球菌及粪肠球菌具有更好的杀菌效果。在SA113菌株中,4×MIC BMS-303141杀菌效果与8×MIC VAN相当,优于8×MIC LZD;在YuSA145中,8×MIC BMS-303141效果最佳,优于8×MIC VAN和8×MIC LZD;在EF16C166和16C51中,4×MIC和8×MIC BMS-303141杀菌效果均优于8×MIC VAN和8×MIC LZD。体外毒性实验显示,BMS-303141具有良好的安全性,不会造成溶血;而且在作用浓度对293T、huh7细胞没有毒性(图6-7)。经BMS-303141处理三株金葡菌的差异蛋白分析,在上调和下调的蛋白中(图8仅列出三株菌共有的),CHS101、SA113、YuSA145三株金葡中均上调的基因有SAOUHSC_02658、SAOUHSC_02630、SAOUHSC_02629、sceD、SAOUHSC_02373,均下调的基因有lip2、adh、sbi、SAOUHSC_02241和hld。综合来看,BMS-303141具有克服耐甲氧西林金黄色葡萄球菌(MRSA)耐药问题的潜能(对16株MRSA和11株MSSA的MIC均为12.5μM),并能杀灭持留菌及抑制或清除生物被膜,有望开发成为高效、广谱的新型抗菌剂。
附图说明
图1是本发明实施例BMS-303141对金黄色葡萄球菌的生长抑制作用结果图;其中A-F分别为SA113、YuSA139、YuSA145、CHS101、CHS736、USA300金黄色葡萄球菌的生长曲线。N=3。数据以Mean±SEM表示。
图2是本发明实施例BMS-303141对粪肠球菌的生长抑制作用结果图;其中A-E分别为EF16C51、EF16C152、EF16C83、OG1RF、EF16C166粪肠球菌的生长曲线。数据以Mean±SEM表示。
图3是本发明实施例的BMS-303141抑制粪金黄色葡萄球菌生物被膜形成的实验结果图;其中,A为不同浓度BMS-303141处理后8株MRSA的OD600值,B为不同浓度BMS-303141处理后8株MRSA1%结晶紫染色后的OD570值,C为不同浓度BMS-303141处理后8株MSSA的OD600值,D为不同浓度BMS-303141处理后8株MSSA 1%结晶紫染色后的OD570值。
图4是本发明实施例的BMS-303141抑制粪肠球菌生物被膜形成的实验结果图;其中,A为不同浓度BMS-303141处理后粪肠球菌的OD600值,B为不同浓度BMS-303141处理后粪肠球菌的1%结晶紫染色后的OD570值。
图5是本发明实施例的不同浓度的BMS-303141与对比例万古霉素、利奈唑胺对金黄色葡萄球菌和粪肠球菌的杀菌效果对比结果图;其中A为SA113菌株,B为YUSA145菌株,C为EF16C166菌株,D为EF16C51菌株。
图6是本发明实施例的BMS-303141药物安全性实验结果图;其中A为溶血状况图,B为溶血率。
图7是本发明实施例的BMS-303141药物对293T、Huh7的细胞毒性结果图;其中A为293T,B为Huh7。
图8是本发明实施例的BMS-303141处理三株金黄色葡萄球菌后的差异蛋白分析结果图;其中A为BMS-303141处理后的CHS101中的蛋白表达水平;B为BMS-303141处理后的SA113中的蛋白表达水平;C为BMS-303141处理后的YuSA145中的蛋白表达水平。
具体实施方式
下面对本发明的较优的实施例作进一步的详细说明。
实施例1
采用常规方法研究BMS-303141对金黄色葡萄球菌、粪肠球菌、表皮葡萄球菌的最低抑制浓度MIC,结果如表1所示。
表1中,A为BMS-303141抗金黄色葡萄球菌MIC;B为BMS-303141抗表皮葡萄球菌MIC;C为BMS-303141抗粪肠球菌MIC;D为BMS-303141对各菌株MIC情况统计表。
从上述表1的结果可见,BMS-303141对多种革兰氏阳性细菌具有比较好的抑制活性,证实BMS-303141具有强效抑制金黄色葡萄球菌、粪肠球菌、表皮葡萄球菌生长的效果,对12株MRSA、12株MSSA以及表皮葡萄球菌的最小抑菌浓度MIC范围为12.5μM;对粪肠球菌为12.5-25μM;对表皮葡萄球菌为3.125-12.5μM。仅从MIC值看BMS-303141对金黄色葡萄球菌与表葡菌的效果较粪肠球菌优越。
表1BMS-303141对多种细菌的MIC
此外,在进行本实施例的同时,还以结构类似物药物NDI-091143、HPN-01,包含苯磺酰胺结构的药物如T0901317、FH535、DC260126、Zafirlukast、FBPase-1inhibitor-1,以及包含或联二苯结构的化合物Erastin2、K-Ras G12C-IN-1进行了抗菌活性的对比,结果如表2所示。通过表2和表1的对比可见,BMS-303141对多种革兰氏阳性细菌具有更好的抑制活性。
表2
实施例2
BMS-303141对金黄色葡萄球菌的生长影响实验。
为了验证BMS-303141是否能够抑制金黄色葡萄球菌生长,我们使用不同浓度的BMS-303141处理金黄色葡萄球菌,在不同时间点检测其OD值。具体步骤为:将金黄色葡萄球菌SA113、YuSA139、YuSA145、CHS101、CHS736、USA300进行过夜培养,将过夜培养的菌液按1:200或1:500稀释加入到特制蜂窝状100孔板中,再将BMS-303141药物分别稀释至一定浓度,等体积加入到孔板中,将孔板放入生长曲线分析仪,连续测定OD600吸光度24h,根据测量值绘制各菌株的生长曲线。N=3。数据以Mean±SEM表示。结果如图1所示,BMS-303141浓度为12.5μM完全抑制MRSA株(YuSA139、YuSA145、CHS736、USA300)及MSSA株(SA113、CHS101)的生长,浓度为6.25μM在CHS736、USA300、CHS101生长初期的前6h的抑制效果较明显。可见,BMS-303141可以高效抑制金黄色葡萄球菌的生长。
实施例3
BMS-303141对粪肠球菌的生长影响实验。
为了验证BMS-303141是否能够抑制粪肠球菌生长,我们使用不同浓度的BMS-303141处理粪肠球菌,在不同时间点检测其OD值。具体步骤包括:将粪肠球菌EF16C51、EF16C152、EF16C83、OG1RF、EF16C166过夜培养,将过夜培养的菌液按1:100稀释加入到特制蜂窝状100孔板中,再将BMS-303141药物按照已测定的MIC值分别稀释至一定浓度,等体积加入到孔板中,将孔板放入生长曲线分析仪,连续测定OD600吸光度24h,根据测量值绘制各菌株的生长曲线。N=3。数据以Mean±SEM表示。结果如图2所示,BMS-303141浓度为25μM时完全抑制粪肠球菌EF16C51、EF16C83及OG1RF的生长。可见,BMS-303141可以高效抑制粪肠球菌的生长。
实施例4
BMS-303141对金黄色葡萄球菌生物被膜形成的影响实验。
生物被膜形成是抗感染治疗的一个难点,因此,评估药物的有效性必须要监测其抑制生物被膜的能力。本实施例中使用不同浓度的BMS-303141处理金黄色葡萄球菌24h后,测定OD600,检测细菌生长状态,固定后,使用结晶紫染色,干燥后测定OD570,检测生物被膜生成。具体步骤包括:将过夜培养的8株MRSA和8株MSSA菌株用TSBG 1:100稀释后加入96孔板中,再加入稀释一定倍数的BMS-303141 100μl,设置空白对照组;37℃静置培养24h后分别测定不同浓度BMS-303141处理后8株MRSA的OD600值和8株MSSA的OD600值;吸去上清,100μl无菌水洗三次,洗去浮游菌;干燥,再用100μl甲醇固定15min;吸去甲醇稍微干燥后加入100μl 1%结晶紫染色15min,洗去结晶紫,烘干后检测分别检测不同浓度BMS-303141处理后8株MRSA形成的生物被膜OD570值和8株MSSA的OD570值。N=3,数据以Mean±SEM表示。*P<0.05,**P<0.01,***P<0.001,#P<0.0001。结果如图3所示,BMS-303141能够在3.125(3.13)及6.25μM浓度下显著性地抑制金黄色葡萄球菌生物被膜形成,甚至对于个别菌株1.56μM浓度便可以显著抑制部分金黄色葡萄球菌生物被膜的形成。可见,BMS-303141可以高效抑制金黄色葡萄球菌生物被膜的形成。
实施例5
BMS-303141对粪肠球菌生物被膜形成的影响实验。
为了检测BMS-303141是否能抑制粪肠球菌生物被膜的形成,同实施例4,使用粪肠球菌做了同样的生物被膜抑制实验。具体步骤包括:将过夜培养的11株粪肠球菌用TSBG 1:100稀释后加入96孔板中,再加入稀释一定倍数的BMS-303141 100μl,设置空白对照组;37℃静置培养24h后分别测定不同浓度BMS-303141处理后粪肠球菌的OD600值和1%结晶紫染色后的OD570值。N=3,数据以Mean±SEM表示。#P<0.0001。结果如图4所示,BMS-303141依然能够在3.125(3.13)及6.25μM浓度下显著性地抑制粪肠球菌的生物被膜,甚至对于个别菌株1.56μM浓度亦能显著抑制部分金黄色葡萄球菌生物被膜的形成。这提示,BMS-303141可能对其他革兰氏阳性细菌同样有效,具有成为广谱抗菌药物的潜力。可见,BMS-303141可以高效抑制粪肠球菌生物被膜的形成。
实施例6
BMS-303141对金黄色葡萄球菌和粪肠球菌的杀菌活性实验。
为了了解BMS-303141对金黄色葡萄球菌、粪肠球菌的杀菌活性,将过夜培养的菌液加入4x MIC和8×MIC浓度的BMS-303141。在37℃、220rpm摇床培养并且分别于3h、6h、12h、24h吸取1mL菌液,用无菌生理盐水梯度稀释并涂布于TSB平板进行菌落计数。结果如图5所示,在SA113中,4×MIC BMS-303141杀菌效果与8×MIC VAN(万古霉素)相当,略优于8×MIC LZD(利奈唑胺);在药物处理YuSA145的24h,4×MIC BMS-303141的杀菌效果与8×MICLZD的效果相似,8×MIC BMS-303141效果最佳,优于8×MIC VAN和8×MIC LZD。而对于粪肠球菌EF16C166和16C51,4×MIC和8×MIC BMS-303141在24h的杀菌效果均优于8×MIC VAN和8×MIC LZD,体现了较大的杀菌优势。由此结果可见,在杀菌活性这一实验中,对个别金黄色葡萄球菌,BMS-303141与现有药物万古霉素和利奈唑胺效果相同(例如SA113,MSSA),对其他金黄色葡萄球菌(YUSA145,MRSA),BMS-303141在24小时的效果优于万古霉素和利奈唑胺,而且对粪肠球菌具有更强的杀菌活性。表明BMS-303141对金黄色葡萄球菌MRSA和粪肠球菌具有更强的杀菌活性。
实施例7
BMS-303141的安全性实验。
为了检测BMS-303141的药物毒性,本实施例使用溶血实验进行检测,具体为:使用不同浓度的BMS-303141加入到含有血细胞的PBS中,37℃孵育1h,离心,取上清,OD540nm处测吸光度。0.5%的Triton X-100作为阳性对照,PBS为阴性对照。计算溶血率:实验组-阴性对照组/阳性对照组-阴性对照组*100%。结果如图6所示,BMS-303141浓度高达50μM时,人红细胞的溶血率低于5%,可见BMS-303141药物安全性较高。
另外,本实施例还检测了BMS-303141对293T、Huh7的细胞毒性。具体为:细胞1.25*104个/孔,铺板24h后,以换液的方式加药,加药24h后,每孔加10μl CCK-8,37℃孵育1.5h,高内涵测定OD450。N=6,数据以Mean±SEM表示。****P<0.0001。实验结果如图7所示,在细胞毒性实验中,BMS-303141浓度为100μM时对293T细胞有明显毒性,而在Huh7细胞中,50μM时对细胞有微弱毒性。可见,BMS-303141在低于50μM的用量下,对293T显示无毒性,对Huh7细胞的毒性较小。
实施例8
BMS-303141对金黄色葡萄球菌的蛋白质组学靶点分析实验。
为了初步筛选BMS-303141可能的靶点,使用1/2×MIC BMS-303141同时处理三株金黄色葡萄球菌16h小时后,收集菌体,裂解,提取蛋白,使用高分辨质谱仪分析蛋白表达水平。结果如图8所示,发现经BMS-303141处理三株金黄色葡萄球菌后的差异蛋白分析,在上调和下调的蛋白中(图8),CHS101、SA113、YuSA145金黄色葡萄球菌中均上调的蛋白有SAOUHSC_02658、SAOUHSC_02630、SAOUHSC_02629、SAOUHSC_02373和sceD,均下调的蛋白有lip2、adh、sbi、SAOUHSC_02241和hld。结果揭示这些基因在调控BMS-303141的抗菌活性过程中占有重要作用。
以上内容是结合具体的优选实施方式对本发明所作的进一步详细说明,不能认定本发明的具体实施只局限于这些说明。对于本发明所属技术领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干简单推演或替换,都应当视为属于本发明的保护范围。
Claims (6)
1. BMS-303141用于制备抗革兰氏阳性细菌感染药物中的应用,其特征在于:所述BMS-303141,CAS编号为943962-47-8;所述抗革兰氏阳性细菌感染为抑制金黄色葡萄球菌、抑制粪肠球菌、抑制表皮葡萄球菌、杀灭金黄色葡萄球菌、杀灭粪肠球菌、抑制金黄色葡萄球菌生物被膜形成、抑制粪肠球菌生物被膜形成中的一种或多种。
2.根据权利要求1所述的BMS-303141用于制备抗革兰氏阳性细菌感染药物中的应用,其特征在于:所述BMS-303141在处理体系中的浓度为不小于3.125μM(1.33μg/ml)。
3.根据权利要求1所述的BMS-303141用于制备抗革兰氏阳性菌感染药物中的应用,其特征在于:所述药物为注射剂、片剂、丸剂、胶囊、悬浮剂、颗粒剂、喷剂或乳剂。
4. BMS-303141用于制备抑制革兰氏阳性菌的涂料中的应用,其特征在于:所述涂料用于医疗器械的表面,所述BMS-303141的CAS编号为943962-47-8,所述抑制革兰氏阳性菌为抑制金黄色葡萄球菌、抑制粪肠球菌、抑制表皮葡萄球菌、杀灭金黄色葡萄球菌、杀灭粪肠球菌、抑制金黄色葡萄球菌生物被膜形成、抑制粪肠球菌生物被膜形成中的一种或多种。
5.根据权利要求4所述的BMS-303141用于制备抑制革兰氏阳性菌的涂料中的应用,其特征在于:所述涂料中,所述BMS-303141的浓度为不小于3.125μM。
6. BMS-303141用于制备抗革兰氏阳性菌抗菌剂的应用,其特征在于:所述BMS-303141的CAS编号为943962-47-8,所述抗革兰氏阳性菌为抑制金黄色葡萄球菌、抑制粪肠球菌、抑制表皮葡萄球菌、杀灭金黄色葡萄球菌、杀灭粪肠球菌、抑制金黄色葡萄球菌生物被膜形成、抑制粪肠球菌生物被膜形成中的一种或多种。
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