CN116549464A - 长链烷基tpp化合物用于制备抗细菌感染药物中的应用 - Google Patents
长链烷基tpp化合物用于制备抗细菌感染药物中的应用 Download PDFInfo
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Abstract
本发明提供了长链烷基TPP化合物用于制备抗细菌感染药物中的应用,所述长链烷基TPP化合物为Mito‑apocynin、Mitoquinone mesylate、MitoTam bromide或MitoTam iodide,所述Mito‑apocynin的CAS编号为1254044‑38‑6;所述Mitoquinone mesylate的CAS编号为845959‑50‑4;所述MitoTam bromide的CAS编号为1634624‑73‑9;所述MitoTam iodide的CAS编号为1634624‑74‑0。本发明的技术方案公开了长链烷基TPP化合物的医药新用途,表现出较佳的抗菌活性。
Description
技术领域
本发明属于医药技术领域,尤其涉及长链烷基TPP化合物用于制备抗细菌感染药物中的应用。
背景技术
ESKAPE病原体(包括粪肠杆菌、金黄色葡萄球菌、肺炎克雷伯菌、鲍曼不动杆菌、铜绿假单胞菌、肠杆菌)是社区获得性和医院感染中常见的条件致病菌,ESKAPE病原菌感染常会伴随较高的发病率、病死率和高昂的治疗费用。ESKAPE突变能力强,传播速度快,耐药情况十分严峻,成为临床抗感染治疗中的一项难题。随着ESKAPE临床分离株耐药性发生率的增加,细菌感染相关疾病的治疗越来越困难。碳青霉烯类、粘菌素和替加环素被认为是对抗这些耐药细菌的最后选择。然而,随着相关耐药基因如碳青霉烯酶基因、磷酸乙醇胺转移酶编码基因mcr-1和tet(X)等耐药基因在临床细菌分离株中的出现,使得临床上用于抗耐药ESKAPE病原菌感染的传统抗生素选择极少。与此同时,在过去的几十年里,由于新药开发的巨大科学和商业挑战,很少有具有独特作用模式的新型抗生素被批准用于临床应用。此外,超过80%的细菌感染伴随着生物被膜的形成,细菌生物被膜群落的三维结构、细胞外基质和细菌间信号传导特征促进细菌的长期定植并有助于生物膜细菌的抗生素耐药性,使得生物被膜相关病原体引起的感染很难根除,造成长期感染并导致严重的并发症。目前迫切需要研究新型抗细菌感染药解决临床耐药菌感染问题。
发明内容
针对以上技术问题,本发明公开了长链烷基TPP(Triphenylphosphine,三苯基膦)化合物用于制备抗细菌感染药物中的应用,这是长链烷基TPP化合物的一种新用途,多种含长链烷基的TPP化合物对革兰氏阳性菌包括金黄色葡萄球菌、表皮葡萄球菌、粪肠球菌、屎肠球菌等以及多种革兰氏阴性菌包括鲍曼不动杆菌、大肠埃希菌、铜绿假单胞菌、肺炎克雷伯菌等临床分离株表现出抑菌活性和杀菌活性,同时可灭杀成熟生物被膜中的细菌,为基于以含长链烷基TPP化合物为先导结构的抗菌药物的开发提供参考依据。
对此,本发明采用的技术方案为:
长链烷基TPP化合物用于制备抗细菌感染药物中的应用,所述长链烷基TPP化合物为Mito-apocynin、Mitoquinone mesylate、MitoTam bromide或MitoTam iodide;所述Mito-apocynin的CAS编号为1254044-38-6,所述Mitoquinone mesylate的CAS编号为845959-50-4,所述MitoTam bromide的CAS编号为1634624-73-9,所述MitoTam iodide的CAS编号为1634624-74-0;所长链烷基TPP化合物具有抑制细菌生长和生物被膜形成的作用。
其中,所述Mito-apocynin(C11)的结构式如式(1)所示:
所述Mitoquinone mesylate(米托蒽醌甲磺酸盐)的结构式如式(2)所示:
所述MitoTam bromide的结构式如式(3)所示:
所述MitoTam iodide的结构式如式(4)所示:
所述细菌包括革兰氏阳性菌和革兰氏阴性菌,所述革兰氏阳性菌包括金黄色葡萄球菌、表皮葡萄球菌、粪肠球菌、屎肠球菌中的至少一种,所述革兰氏阴性菌包括鲍曼不动杆菌、大肠埃希菌、铜绿假单胞菌、肺炎克雷伯菌中的至少一种。
上述化合物中,Mito-apocynin(C11)是通过由11个碳原子组成的烷基链将香草乙酮(apocynin)偶联到线粒体靶向的亲脂基团三苯基膦(TPP)。在Mito-apocynin(C11)中存在的高度亲脂性阳离子部分使其具备更好的细胞渗透性和选择性地靶向线粒体。TPP通过长链烷基与香草乙酮偶联,促进了香草乙酮在线粒体中的积累,使得低剂量的Mito-apocynin(C11)可显著改善小鼠的协调运动功能和嗅觉功能。研究证实,Mito-apocynin(C11)选择性靶向线粒体,具有神经保护作用。Mito-apocynin(C11)可预防嗅觉减退,纠正运动功能的缺陷。米托蒽醌甲磺酸盐(Mitoquinone mesylate)是强效抗氧化剂泛醌通过10碳烷基链与线粒体靶向的三苯基膦连接。在脓毒症动物模型中,Mitoquinone mesylate已被证明可抑制肾、肝、肺、肠屏障和心脏功能障碍。MitoTam bromide和MitoTam iodide都是他莫昔芬衍生物,为电子传递链(ETC)抑制剂,抑制衰老细胞中的线粒体膜电位变化并影响线粒体形态,均含10碳烷基链偶连三苯基膦,可以抑制乳腺癌细胞中呼吸复合物(CI-respiration)和超复合物(SCs)的形成。但是目前,关于Mito-apocynin(C11)、Mitoquinonemesylate、MitoTam bromide和MitoTam iodide等长链烷基TPP化合物的抗菌活性未见报道。
而本发明人通过大量实验发现,多种长链烷基TPP化合物(含Mito-apocynin(C11)、Mitoquinone mesylate、MitoTam bromide和MitoTam iodide等)对多种革兰氏阳性菌包括金黄色葡萄球菌、表皮葡萄球菌、粪肠球菌、屎肠球菌等以及多种革兰氏阴性菌包括鲍曼不动杆菌、大肠埃希菌、铜绿假单胞菌、肺炎克雷伯菌等临床分离株表现出抑菌活性,而且比万古霉素表现出更显著的杀菌活性,特别是对生物被膜中的细菌具有较强的灭杀活性。在培养基中添加细菌膜磷脂成份可以剂量依赖性的方式降低长链烷基TPP代表性化合物Mito-apocynin(C11)的抑菌活性,说明长链烷基TPP化合物的抑菌活性是靶向细菌细胞膜的。此外,长链烷基TPP代表性化合物Mito-apocynin(C11)对人类细胞的毒性较小,对血管内皮细胞HUEVC、人肝星形细胞LX2、A549以及人肾上皮细胞系293T增殖的半抑制浓度(IC50)显著高于其对细菌的最低抑制浓度(MIC)值。这些结果表明长链烷基TPP化合物在临床抗感染治疗中具有潜在应用价值。
作为本发明的进一步改进,长链烷基TPP化合物在处理体系中的浓度为不小于0.50μg/mL。进一步的,所述长链烷基TPP化合物在处理体系中的浓度为不小于1μg/mL。进一步的,所述长链烷基TPP化合物在处理体系中的浓度为0.5~128μg/mL。
作为本发明的进一步改进,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。
本发明还公开了长链烷基TPP化合物用于制备抑菌涂料中的应用,所述涂料用于医疗器械的表面,所述长链烷基TPP化合物为Mito-apocynin、Mitoquinone mesylate、MitoTam bromide或MitoTam iodide;所述Mito-apocynin的CAS编号为1254044-38-6,所述Mitoquinone mesylate的CAS编号为845959-50-4,所述MitoTam bromide的CAS编号为1634624-73-9,所述MitoTam iodide的CAS编号为1634624-74-0;所长链烷基TPP化合物具有抑制细菌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,所述长链烷基TPP化合物的浓度不小于0.50μg/mL。
本发明还公开了长链烷基TPP化合物用于制备抗菌剂的应用,所述长链烷基TPP化合物为Mito-apocynin、Mitoquinone mesylate、MitoTam bromide或MitoTam iodide;所述Mito-apocynin的CAS编号为1254044-38-6,所述Mitoquinone mesylate的CAS编号为845959-50-4,所述MitoTam bromide的CAS编号为1634624-73-9,所述MitoTam iodide的CAS编号为1634624-74-0;所长链烷基TPP化合物具有抑制细菌生长和生物被膜形成的作用。。采用此技术方案,该抗菌剂可以对多种革兰氏阳性菌包括金黄色葡萄球菌、表皮葡萄球菌、粪肠球菌、屎肠球菌等以及多种革兰氏阴性菌包括鲍曼不动杆菌、大肠埃希菌、铜绿假单胞菌、肺炎克雷伯菌等具有良好的抑菌或杀菌作用。
本发明还公开了一种抗菌剂,包含长链烷基TPP化合物,所述长链烷基TPP化合物,包括但不限于Mito-apocynin(C11)、Mitoquinone mesylate、MitoTam bromide和MitoTamiodide等。采用此技术方案,该抗菌剂可以对多种革兰氏阳性菌包括金黄色葡萄球菌、表皮葡萄球菌、粪肠球菌、屎肠球菌等以及多种革兰氏阴性菌包括鲍曼不动杆菌、大肠埃希菌、铜绿假单胞菌、肺炎克雷伯菌等具有良好的抑菌或杀菌作用。
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长链烷基TPP化合物的医药新用途,长链烷基TPP化合物对多种革兰氏阳性菌包括金黄色葡萄球菌、表皮葡萄球菌、粪肠球菌、屎肠球菌等以及多种革兰氏阴性菌包括鲍曼不动杆菌、大肠埃希菌、铜绿假单胞菌、肺炎克雷伯菌等较佳的抗菌活性,特别是对革兰氏阳性菌的抑制效果更为明显,且比万古霉素表现出更显著的杀菌活性,而且能够灭杀生物被膜中的细菌。MIC剂量下长链烷基TPP化合物对人血管内皮细胞HUEVC、人肝星形细胞LX2、人类肺泡基底上皮细胞A549以及人肾上皮细胞系293T的毒性较小。这些结果提示长链烷基TPP化合物具备治疗多种细菌感染的可能性。并且,长链烷基TPP化合物的MIC与临床常用抗生素相当,适宜临床使用。可见长链烷基TPP化合物在临床抗细菌感染治疗中具有潜在应用价值。
附图说明
图1是本发明实施例添加长链烷基TPP化合物Mito-apocynin(C11)、Mitoquinonemesylate、MitoTam bromide、MitoTam iodide后对革兰氏阳性菌金黄色葡萄球菌和粪肠球菌,以及革兰氏阴性菌包括鲍曼不动杆菌和大肠埃希菌的生长曲线,其中(a)~(d)分别为Mito-apocynin(C11)、Mitoquinone mesylate、MitoTam bromide、MitoTam iodide对金黄色葡萄球菌YUSA145生长曲线的影响,(e)~(h)为Mito-apocynin(C11)、Mitoquinonemesylate、MitoTam bromide、MitoTam iodide对粪肠球菌OG1RF生长曲线的影响,(i)~(l)为Mito-apocynin(C11)、Mitoquinone mesylate、MitoTam bromide、MitoTam iodide对鲍曼不动杆菌AB2218生长曲线的影响,(m)~(p)为Mito-apocynin(C11)、Mitoquinonemesylate、MitoTam bromide、MitoTam iodide对大肠埃希菌ECO2219生长曲线的影响。
图2是本发明实施例长链烷基TPP化合物Mito-apocynin(C11)、Mitoquinonemesylate、MitoTam bromide、MitoTam iodide对甲氧西林敏感金黄色葡萄球菌(MSSA)临床株CHS101、耐甲氧西林金黄色葡萄球菌(MRSA)临床株YUSA145和粪肠球菌临床株EF16C51杀菌曲线分析,图中,(a)~(c)为Mito-apocynin(C11),(d)~(f)为Mitoquinone mesylate,(g)~(i)为MitoTam bromide,(j)~(l)为MitoTam iodide。
图3是本发明实施例的激光共聚焦显微镜观察下4×MIC浓度Mito-apocynin(C11)对金黄色葡萄球菌临床株YUSA145生物被膜中细菌灭杀作用结果。
图4是本发明实施例的Mito-apocynin(C11)对金黄色葡萄球菌的YUSA145的细胞膜通透性的影响;其中(a)为对照样的浮游菌照片,(b)为1×MIC处理后的浮游菌照片,(c)是2×MIC处理后的浮游菌照片,(d)是染色荧光对比表。
图5是本发明实施例的添加不同细菌膜磷脂成份对Mito-apocynin(C11)抑菌活性的影响。图中CL代表心磷脂,PG代表磷脂酰甘油,PE代表磷脂酰乙醇胺;其中(a)为YUSA145,(b)为ATCC29213。
图6是本发明实施例的Mito-apocynin(C11)对人血管内皮细胞HUEVC、人肝星形细胞LX2、人类肺泡基底上皮细胞A549以及人肾上皮细胞系293T细胞毒性检测结果;其中,(a)为人血管内皮细胞HUEVC,(b)为人肝星形细胞LX2,(c)为人类肺泡基底上皮细胞A549,(d)为人肾上皮细胞系293T。
图7是本发明实施例的Mito-apocynin(C11)对金黄色葡萄球菌感染引起脓肿的抗感染疗效结果,(a)为细菌负荷统计结果,(b)为伤口面积统计,(c)为感染伤口照片。
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
1.1菌株来源
本实施例中使用的102株革兰氏阳性菌(包括20株MRSA,20株MSSA,22株表皮葡萄球菌,19株屎肠球菌和21株粪肠球菌)和86株革兰氏阴性菌(包括21株鲍曼不动杆菌、20株铜绿假单胞菌、20株肺炎克雷伯菌和25株大肠埃希菌)临床株收集于医院不同住院患者。所有临床菌株都通过Phoenix 100自动微生物鉴定系统鉴定,继代培养后采用基质辅助激光解吸电离/飞行时间质谱(MALDI-TOF-MS)对所有菌株进行重新鉴定。质量控制菌株金黄色葡萄球菌ATCC29213购自ATCC菌株库。
1.2主要仪器和试剂
主要仪器:微量移液器,Phoenix-100全自动细菌鉴定/药敏系统,全自动生物质谱检测系统IVD MALDI Biotyper,全自动生长曲线分析仪,CAMHB培养基,TSB培养基,激光扫描共聚焦显微镜FV3000。
主要试剂:Mito-apocynin(C11)、Mito-apocynin(C2)、Mitoquinone mesylate、MitoTam bromide、MitoTam iodide、Mito-LND、AP39、(4-Carboxybutyl-d4)triphenylphosphonium、Dasotraline(hydrochloride)、XMD-17-51(Trifluoroacetate)、结晶紫,LIVE/DEAD BacLightTM荧光染料,葡萄糖。
实施例1
本实施例中,采用96孔板高通量筛选发现长链烷基TPP化合物Mito-apocynin(C11)对金黄色葡萄球菌和粪肠球菌的生长具有显著抑制活性。具体步骤为:
取过夜培养菌液(金黄色葡萄球菌ATCC29213和粪肠球菌OG1RF)用比浊杯调整浊度至0.5麦氏(菌量约为1.0-1.5×108cfu/mL)。取菌液同CAMHB培养基1:200稀释后加入96孔板,每行12孔,每孔200μL。添加Mito-apocynin(C11)稀释至50μM,第12孔加入200μLCAMHB培养基设为阴性对照。37℃培养24小时后观察结果,以肉眼不能看见细菌生长的孔中添加的化合物被认为具有潜在的抑菌活性。并以添加Mito-LND、AP39、(4-Carboxybutyl-d4)triphenylphosphonium、Dasotraline(hydrochloride)、XMD-17-51(Trifluoroacetate)作为对比例。
本实施例中,添加50μM Mito-apocynin(C11)的金黄色葡萄球菌ATCC29213和粪肠球菌OG1RF在24小时后培养基都表现为澄清,未观察到细菌有生长,OD600都小于0.1。而添加Mito-LND、AP39、(4-Carboxybutyl-d4)triphenylphosphonium、Dasotraline(hydrochloride)、XMD-17-51(Trifluoroacetate)等都仍有细菌有生长。
可见Mito-apocynin(C11)对金黄色葡萄球菌和粪肠球菌具有潜在的抑菌活性。
实施例2
采用微量肉汤稀释法检测多种含有TPP的Mito-apocynin(C11)结构类似物对多株革兰氏阳性菌(包括2株金黄色葡萄球菌、2株粪肠球菌)和多株革兰氏阴性菌(包括2株鲍曼不动杆菌和2株大肠埃希菌)的MIC。
在上述实施例的基础上,选择Mito-apocynin(C11)结构类似的TPP化合物Mito-apocynin(C2)、Mitoquinone mesylate、MitoTam bromide、MitoTam iodide、Mito-LND、AP39、(4-Carboxybutyl-d4)triphenylphosphonium为研究对象,具体步骤为:
取过夜培养菌液用比浊杯调整浊度至0.5麦氏(菌量约为1.0-1.5×108cfu/mL)。取菌液同CAMHB培养基1:100稀释后加入96孔板,每行12孔,药物设置10个梯度孔(128,64,32,16,8,4,2,1,0.5,0.25μg/mL),第11孔加入200μL上述菌液设为阳性对照,第12孔加入200μL CAMHB培养基设为阴性对照。37℃培养18小时后观察结果,以肉眼不能看见菌液沉淀的药物浓度孔计算为MIC值。
本实施例结果如表1所示多种含有TPP的Mito-apocynin(C11)结构类似物包括Mitoquinone mesylate(CAS编号为845959-50-4)、MitoTam bromide(CAS编号为1634624-73-9)、MitoTam iodide(CAS编号为1634624-74-0)、Mito-LND(CAS编号为2361564-49-8)、AP39(CAS编号为1429061-80-2)对金黄色葡萄球菌、粪肠球菌、鲍曼不动杆菌和大肠埃希菌都表现出广谱抑菌活性;然而,携带短链烷基的三苯基膦(TPP)衍生物Mito-apocynin(C2)和(4-Carboxybutyl-d4)triphenylphosphonium(bromide)却没有抑菌活性,说明TPP化合物的抑菌活性与其携带烷基链的长度相关,只有长链烷基TPP化合物才能表现出较佳的抗菌活性。
表1多种含长链烷基TPP化合物对革兰氏阳性菌和革兰氏阴性菌临床株的MIC值结果(μg/mL)
注:S.aureus:金黄色葡萄球菌;E.faecalis:粪肠球菌;A.baumannii:鲍曼不动杆菌;E.coli:大肠埃希菌。
实施例3
本实施例中,采用微量肉汤稀释法检测长链烷基TPP代表性化合物Mito-apocynin(C11)对102株临床分离革兰氏阳性菌株(包括20株甲氧西林敏感金黄色葡萄球菌MSSA、20株耐甲氧西林金黄色葡萄球菌MRSA、22株表皮葡萄球菌、21株粪肠球菌和19株屎肠球菌)、86株革兰氏阴性菌(包括21株鲍曼不动杆菌、20株铜绿假单胞菌、20株肺炎克雷伯菌和25株大肠埃希菌)的最低抑制浓度MIC,具体步骤为:
取过夜培养菌液用比浊杯调整浊度至0.5麦氏(菌量约为1.0-1.5×108cfu/mL)。取菌液同CAMHB培养基1:100稀释后加入96孔板,每行12孔,药物设置10个梯度孔(128,64,32,16,8,4,2,1,0.5,0.25μg/mL),第11孔加入200μL上述菌液设为阳性对照,第12孔加入200μL CAMHB培养基设为阴性对照。各抗菌药物的MIC值测定培养条件和时间按照CLSI指南进行,37℃培养18小时后观察结果,以肉眼不能看见菌液沉淀的药物浓度孔计算为MIC值。
本实施例中,Mito-apocynin(C11)对金黄色葡萄球菌、表皮葡萄球菌、粪肠球菌、屎肠球菌等革兰氏阳性菌的MIC值结果如表2所示,可见Mito-apocynin(C11)对多种革兰氏阳性菌具有较佳的抑菌活性,MIC值主要分布在1μg/mL到4μg/mL之间,其中对表皮葡萄球菌的抑制效果最佳,MIC50为1μg/mL。Mito-apocynin(C11)对鲍曼不动杆菌、铜绿假单胞菌、肺炎克雷伯菌和大肠埃希菌等革兰氏阴性菌的MIC值结果如表3所示,Mito-apocynin(C11)对所有的鲍曼不动杆菌和大肠埃希菌临床株都表现出抑菌活性,MIC值主要分布在32μg/mL和64μg/mL。
表2革兰氏阳性菌临床株对Mito-apocynin(C11)的MIC值分布
注:MIC:最小抑菌浓度;MSSA:甲氧西林敏感金黄色葡萄球菌;MRSA:耐甲氧西林金黄色葡萄球菌;E.faecalis:粪肠球菌;S.epidermidis:表皮葡萄球菌;E.faecium:屎肠球菌;n为所测菌株数量。
表3革兰氏阴性菌临床株对Mito-apocynin(C11)的MIC值分布
注:K.peneumoniae:肺炎克雷伯菌;E.coli:大肠埃希菌;A.baumannii:鲍曼不动杆菌;P.aeruginosa:铜绿假单胞菌;n为所测菌株数量。
实施例4
长链烷基TPP化合物Mito-apocynin(C11)、Mitoquinone mesylate、MitoTambromide、MitoTam iodide对革兰氏阳性菌和革兰氏阴性菌的生长影响实验。
为了验证长链烷基TPP化合物Mito-apocynin(C11)、Mitoquinone mesylate、MitoTam bromide和MitoTam iodide是否能够抑制细菌的生长,我们使用不同亚抑菌浓度的Mito-apocynin(C11)、Mitoquinone mesylate、MitoTam bromide、MitoTam iodide分别处理金黄色葡萄球菌YUSA145、粪肠球菌株OG1RF、鲍曼不动杆菌AB2218和大肠埃希菌ECO2219,在不同时间点检测其OD值,具体步骤为:取过夜培养菌液用胰蛋白胨大豆肉汤(TSB)培养基稀释1000倍后加入96孔板,添加不同浓度(1/16×,1/8×,1/4×,1/2×和1×)Mito-apocynin(C11)、Mitoquinone mesylate、MitoTam bromide或MitoTam iodide后置于全自动生长曲线分析仪中,每间隔1小时测定600nm波长吸光度(OD600)吸光值,以检测培养上清液中浮游菌含量,孵育温度为37℃,绘制生长曲线。
生长曲线分析如图1所示,可见在1/2×MIC浓度下,Mito-apocynin(C11)、Mitoquinone mesylate、MitoTam bromide、MitoTam iodide会抑制金黄色葡萄球菌、粪肠球菌和鲍曼不动杆菌浮游菌的生长;而浓度达到1×MIC时,金黄色葡萄球菌、粪肠球菌、鲍曼不动杆菌和大肠埃希菌的生长被完全抑制,这些结果初步表明长链烷基TPP化合物Mito-apocynin(C11)、Mitoquinone mesylate、MitoTam bromide和MitoTam iodide具有作为抗细菌感染药物的潜力。
实施例5
Mito-apocynin(C11)对革兰氏阳性菌杀菌活性的时间和剂量的影响实验。
本实施例中研究长链烷基TPP化合物Mito-apocynin(C11)、Mitoquinonemesylate、MitoTam bromide和MitoTam iodide对革兰氏阳性菌抗菌活性的时间和剂量依赖效应,并与临床抗生素万古霉素的活性进行比较,具体步骤包括:
将对数期(OD600=0.5)的MSSA临床株CHS101、MRSA临床株YUSA145、粪肠球菌临床株EF16C51菌液稀释100倍,分别与2×,4×,8×MIC的长链烷基TPP化合物Mito-apocynin(C11)、Mitoquinone mesylate、MitoTam bromide和MitoTam iodide、4×MIC的万古霉素后置于摇床200rpm孵育。随后,分别在0、2、6、10、24小时采集样品利用无菌生理盐水进行连续梯度稀释,并涂布在TSB平板上37℃孵育,24小时后菌落计数。菌落计数以fcu/mL表示。
得到的杀菌曲线分析如图2所示,可见长链烷基TPP化合物Mito-apocynin(C11)、Mitoquinone mesylate、MitoTam bromide和MitoTam iodide在2×MIC就可以观察到对金黄色葡萄球菌和粪肠球菌有显著的杀菌效果,在10小时内细菌计数都降低到检测下限,杀菌效果强于4×MIC万古霉素。
实施例6
本实施例采用荧光染色和激光共聚焦显微镜观察法,研究Mito-apocynin(C11)对金黄色葡萄球菌株的成熟生物被膜活性,具体步骤为:
采用玻底培养皿构建生物被膜,通过激光共聚焦显微镜观察生物被膜中的活菌变化,步骤简述如下:用TSBG培养基200倍稀释金黄色葡萄球菌临床MRSA株YUSA145过夜摇培的菌液,20mm玻底培养皿中加入2mL稀释后的菌液,37℃静置培养24小时使其形成成熟的生物被膜,吸出培养基,用无菌生理盐水洗3次后,加入含4×MIC Mito-apocynin(C11)的TSBG培养基继续培养24小时,无菌PBS洗涤后,然后加入Live/Dead BacLightTM荧光染液,室温下避光静置染色30分钟,随后在激光共聚焦显微镜下观察并拍照。
LIVE/DEAD BacLightTM荧光染料包含两种不同的核酸染料,可将质膜完整的活细菌与质膜不完整的死细菌快速区分开来。其中碘化丙啶(PI)用于检测膜渗透性,当其通过被破坏的细胞膜进入细菌与核酸结合时,荧光强度会增加。
用激光共聚焦显微镜观察生物被膜,结果如图3所示,可见当4×MIC的Mito-apocynin(C11)处理时,金黄色葡萄球菌株生物被膜中的活菌数(绿色荧光)大大降低,死菌(红色荧光)数比例极高,表明Mito-apocynin(C11)能对金黄色葡萄球菌成熟生物被膜中的细菌具有较强的灭杀作用。
实施例7
本实施例为Mito-apocynin(C11)对金黄色葡萄球菌的YUSA145的细胞膜通透性的研究实验,具体步骤为:
将对数期的革兰氏阳性菌YUSA145细胞调整到OD600=0.05,与LIVE/DEADBacLightTM荧光染料在黑暗中孵育。而后对悬浮液用不同浓度Mito-apocynin(C11)处理(最终浓度为1/2×,1×和2×MIC),以0.1% DMSO作为对照,1小时后用酶标仪监测碘化丙啶(PI)染色荧光值,同时激光共聚焦显微镜观察处理后的浮游菌并拍照。
荧光强度的监测结果如图4所示,发现Mito-apocynin(C11)处理后的金黄色葡萄球菌YUSA145的红色荧光细菌的比例显著升高,荧光值也呈现梯度升高,表明细胞膜通透性改变,说明Mito-apocynin(C11)对金黄色葡萄球菌细胞膜有损伤作用。
实施例8
本实施例中研究Mito-apocynin(C11)作用于细菌细胞膜发货抑菌活性,具体步骤包括:
本实施例中,为了分析Mito-apocynin(C11)的抑菌活性是否跟细胞膜相关,采用棋盘式微量肉汤稀释法检测不同浓度的细菌细胞膜磷脂成分磷脂酰甘油(PG)、磷脂酰乙醇胺(PE)和心磷脂(CL)对Mito-apocynin(C11)最低抑制浓度MIC的影响,具体步骤为:
取过夜金黄色葡萄球菌标准株ATCC29213和MRSA临床株YUSA145培养菌液用比浊杯调整浊度至0.5麦氏(菌量约为1.0-1.5×108cfu/mL)。取菌液同CAMHB培养基1:100稀释后加入96孔板,每行12孔,Mito-apocynin(C11)设置10个梯度孔(128,64,32,16,8,4,2,1,0.5,0.25μg/mL),第11孔加入200μL上述菌液设为阳性对照,第12孔加入200μL CAMHB培养基设为阴性对照;细胞膜磷脂成分设置8个梯度孔(128,64,32,16,8,4,2,1μg/mL)。各抗菌药物的MIC值测定培养条件和时间按照CLSI指南进行,37℃培养18小时后观察结果,以肉眼不能看见菌液沉淀的药物浓度孔计算为MIC值。
得到的结果以不同磷脂的浓度为横坐标,以Mito-apocynin(C11)的MIC浓度倍数变化为纵坐标作图,结果如图5所示,外源性在培养基中添加细菌细胞膜磷脂降低了Mito-apocynin(C11)的抑菌活性,并呈剂量依赖性,可见Mito-apocynin(C11)是作用于细菌细胞膜发挥抑菌活性的。
实施例9
本实施例为Mito-apocynin(C11)对人血管内皮细胞HUEVC、人肝星形细胞LX2、人类肺泡基底上皮细胞A549以及人肾上皮细胞系293T细胞毒性的影响实验,具体步骤为:
在96孔板中配制100μL的人血管内皮细胞HUEVC、人肝星形细胞LX2、人类肺泡基底上皮细胞A549或人肾上皮细胞系293T细胞毒性细胞悬液。将培养板放在培养箱预培养24小时(37℃,5% CO2)。向培养板加入10μL不同浓度的Mito-apocynin(C11),设置8个梯度孔(64,32,16,8,4,2,1,0.5μg/mL)。将培养板在培养箱孵育24小时,向每孔加入10μL CCK-8溶液。将培养板在培养箱内孵育1-4小时。用酶标仪测定在450nm处的吸光度。然后通过吸光度计算细胞活力。
CCK-8试剂盒,是一种基于WST-8(化学名:2-(2-甲氧基-4-硝苯基)-3-(4-硝苯基)-5-(2,4-二磺基苯)-2H-四唑单钠盐)的广泛应用于细胞增殖和细胞毒性的快速高灵敏度检测试剂盒。其工作原理为:在电子耦合试剂存在的情况下,可以被线粒体内的脱氢酶还原生成高度水溶性的橙黄色的甲臜产物(formazan)。颜色的深浅与细胞的增殖成正比,与细胞毒性成反比。使用酶标仪在450nm波长处测定OD值,间接反映活细胞数量。Mito-apocynin(C11)对HUEVC、LX2、A549和293T细胞毒性的结果如图6所示,其IC50分别为,3.87μg/mL、5.33μg/mL、2.85μg/Ml和5.26μg/mL,可见,Mito-apocynin(C11)的细胞毒性较小,高于其对所有检测的大部分革兰氏阳性菌临床株的MIC值,具有潜在的临床抗感染应用潜力。
实施例10
本实施例为Mito-apocynin(C11)对金黄色葡萄球菌YUSA145感染引起的皮肤脓肿的抗感染治疗实验,具体步骤为:
采用7-8周龄的BALB/C小鼠建立金黄色葡萄球菌感染皮肤脓肿模型。为了制备接种菌液,在5mL培养液中培养金黄色葡萄球菌YUSA145,在37℃下孵育16小时,而后1:100稀释再接种到50mL新鲜培养基中,在37℃下摇动培养至OD600至0.5左右。离心10分钟收集细菌,重新悬浮在一半体积的0.9%生理盐水中,部分倍比稀释,涂板计数。用镊子在棉球上蘸取异氟烷置于笼内麻醉小鼠,待小鼠失去知觉后取出。用脱毛膏脱去背部毛发(20mm×20mm),而用50μL细菌悬液(细菌计数约为5×108CFU)进行皮下注射形成囊肿。接种感染后1小时,直接在感染区皮下施药(剂量为25mg/kg)。每天按早晚各一次进行给药。第三天颈椎脱臼处死小鼠,用卡尺测量脓肿(包括可见的肿胀和发炎肿块),切除皮肤脓肿(包括所有累积的脓液),匀浆5分钟,并通过连续稀释法测定细菌计数。
结果如图7所示,可见,25mg/kg剂量的Mito-apocynin(C11)对金黄色葡萄球菌YUSA145感染引起的皮肤脓肿有显著的抗感染效果,感染面积和细菌负荷相比生理盐水处理对照组都显著的降低。
上述所有的实验均使用GraphPad Prism 8.0软件进行数据处理及绘制图像。P<0.05被认为具有统计学差异。
通过上述结果可见,以Mito-apocynin(C11)为代表的长链烷基TPP化合物对临床常见革兰氏阳性菌和革兰氏阴性菌都表现出抑菌活性,特别是对革兰氏阳性菌(包括金黄色葡萄球菌、表皮葡萄球菌、粪肠球菌、屎肠球菌)抑菌效果极佳,Mito-apocynin(C11)对102株临床分离革兰氏阳性菌株的MIC值≤4μg/mL。此外,Mito-apocynin(C11)对金黄色葡萄球菌和粪肠球菌有显著杀菌效果,即使在2×MIC浓度下,在6小时内细菌计数降低到检测下限。MIC剂量下Mito-apocynin(C11)对HUEVC、LX2、A549和293T细胞的毒性较小。这些结果提示以Mito-apocynin(C11)为代表的长链烷基TPP化合物具备治疗临床细菌感染疾病的可能性。并且,以多种长链烷基TPP化合物(含Mito-apocynin(C11)、Mitoquinone mesylate、MitoTam bromide和MitoTam iodide等)的MIC与临床常用抗生素相当,适宜临床使用。
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 (7)
1.长链烷基TPP化合物用于制备抗细菌感染药物中的应用,其特征在于:所述长链烷基TPP化合物为Mito-apocynin、Mitoquinone mesylate、MitoTam bromide或MitoTamiodide;所述Mito-apocynin的CAS编号为1254044-38-6,所述Mitoquinone mesylate的CAS编号为845959-50-4,所述MitoTam bromide的CAS编号为1634624-73-9,所述MitoTamiodide的CAS编号为1634624-74-0;所长链烷基TPP化合物具有抑制细菌生长和生物被膜形成的作用。
2.根据权利要求1所述的长链烷基TPP化合物用于制备抗细菌感染药物中的应用,其特征在于:所述细菌包括革兰氏阳性菌和革兰氏阴性菌,所述革兰氏阳性菌包括金黄色葡萄球菌、表皮葡萄球菌、粪肠球菌、屎肠球菌中的至少一种,所述革兰氏阴性菌包括鲍曼不动杆菌、大肠埃希菌、铜绿假单胞菌、肺炎克雷伯菌中的至少一种。
3.根据权利要求2所述的长链烷基TPP化合物用于制备抗细菌感染药物中的应用,其特征在于:所述长链烷基TPP化合物在处理体系中的浓度为不小于0.50μg/mL。
4.根据权利要求2所述的长链烷基TPP化合物用于制备抗细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。
5.长链烷基TPP化合物用于制备抑菌涂料中的应用,其特征在于:所述涂料用于医疗器械的表面,所述长链烷基TPP化合物为Mito-apocynin、Mitoquinone mesylate、MitoTambromide或MitoTam iodide;所述Mito-apocynin的CAS编号为1254044-38-6,所述Mitoquinone mesylate的CAS编号为845959-50-4,所述MitoTam bromide的CAS编号为1634624-73-9,所述MitoTam iodide的CAS编号为1634624-74-0;所长链烷基TPP化合物具有抑制细菌生长和生物被膜形成的作用。。
6.根据权利要求5所述的长链烷基TPP化合物用于制备抑菌涂料中的应用,其特征在于:所述涂料中,所述长链烷基TPP化合物的浓度不小于0.50μg/mL。
7.长链烷基TPP化合物用于制备抗菌剂的应用,其特征在于:所述长链烷基TPP化合物为Mito-apocynin、Mitoquinone mesylate、MitoTam bromide或MitoTam iodide;所述Mito-apocynin的CAS编号为1254044-38-6,所述Mitoquinone mesylate的CAS编号为845959-50-4,所述MitoTam bromide的CAS编号为1634624-73-9,所述MitoTam iodide的CAS编号为1634624-74-0;所长链烷基TPP化合物具有抑制细菌生长和生物被膜形成的作用。
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