CN110214016A - 用于治疗细菌感染的治疗组合 - Google Patents

用于治疗细菌感染的治疗组合 Download PDF

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CN110214016A
CN110214016A CN201880008381.4A CN201880008381A CN110214016A CN 110214016 A CN110214016 A CN 110214016A CN 201880008381 A CN201880008381 A CN 201880008381A CN 110214016 A CN110214016 A CN 110214016A
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combination
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rifampin
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C·法尔恰尼
A·皮尼
L·布拉奇
J·布鲁内提
G·罗索里尼
S·波利尼
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Setrans Co Ltd
SETLANCE Srl
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Abstract

本文公开了抗菌肽和抗生素药物的治疗组合，用于治疗由革兰氏阴性病原体引起的感染，包括对常见抗生素有抗性的细菌菌株。还公开了含有抗菌肽和抗生素的药物制剂和组合物。

Description

用于治疗细菌感染的治疗组合
本发明提供抗菌肽和抗生素药物(Antibiotic drug)的治疗组合，用于治疗由革兰氏阴性菌引起的感染。所述治疗组合对于对常见抗生素有抗性的细菌菌株显示协同活性。本发明进一步提供含有所述抗菌肽和抗生素并混合有适合的赋形剂的药物制剂和组合物。
发明背景
新“前抗生素”时代的全球威胁现已得到社会各界人士的认可，不仅是科学界，还有公共卫生机构和政府。由于多药耐药性(MDR)和极度耐药性(XDR)细菌病原体的传播，即使是常见的感染也可能转变为无法使用标准治疗(standard of care)抗生素治疗的病症[1-2]。
现在人们正极尽努力面对这一迫切的医疗需求。需要新的抗生素与新的组合疗法以控制MDR和XDR病原体引起的感染[3]。
SET-M33是一种抗微生物肽(AMP)，近年来被广泛研究[4-7]。其在体外和体内对革兰氏阴性菌具有活性，同时缺乏免疫原性[8]和溶血活性，且在人细胞和小鼠中显示出可接受的毒性谱[9-10]。该AMP目前正作为对抗MDR和XDR革兰氏阴性感染的新治疗选择被开发。事实上，SET-M33已经显示出针对包括来自囊性纤维化患者的分离物在内的许多革兰氏阴性MDR和XDR临床分离物的效力，同时还表现出根除生物膜的能力[6]。
组合抗感染化合物以扩大活性谱、改善治疗效果且甚至减少耐药性的出现，是抗微生物化疗的一个明确策略[11-13]。
在之前的研究中已经考察了AMP、尤其是粘菌素与不同抗微生物剂组合的协同活性。粘菌素已经常被证明与利福平和碳青霉烯类协同对抗革兰氏阴性菌，包括耐碳青霉烯的肺炎克雷伯氏菌(K.pneumoniae)和革兰氏阴性非发酵菌(fermenters)[21-23]，以及与氨曲南、氟喹诺酮和氨基糖苷类以较低程度对抗[21，24-26]。其它AMP也同样被报道为多与利福平和B-内酰胺类组合具有协同效应[20，27-28]，而与其它试剂的协同效应数据仍更为有限或存在争议[29-31]。
现有技术
WO2006/006195公开了抗菌肽，包括肽QKKIRVRLSA(M6)，其表现出针对几种细菌种类的抗微生物活性，具有降低的细胞毒性和低溶血速率。所述肽是线性形式或多聚化在聚丙烯酰胺、葡聚糖或乙二醇单元的骨架上，且优选所述肽以多抗原肽(Multiple AntigenicPeptides)的形式提供。
EP2344178公开了抗菌肽序列，包括序列KKIRVRLSA，其对应于WO2006/006125中所公开的缺失第一氨基酸GLN的M6肽。除改善的稳定性和批次间均匀性外，所述肽表现出更好的抗微生物活性，并且以单体或树枝状(Dendrimeric)结构、尤其是多抗原肽形式提供。
WO2010/038220公开了抗微生物肽，包括KKIRVRLSA肽，其为单体或树枝状结构，优选为多抗原肽形式。
EP2595496公开了肽KKIRVRLSA，其特征在于所有氨基酸均呈D-构型(D-M33)，或者以线性形式或多聚化在聚丙烯酰胺、葡聚糖或乙二醇单元的骨架上。
发明详述
在本发明中，已经在体外评估了肽SET-M33——也称为“M33”且依据单字母氨基酸码具有序列KKIRVRLSA——与标准治疗抗生素组合后对革兰氏阴性病原体的抗微生物活性。
令人惊讶的发现是，所述肽与利福平、美罗培南、氨曲南和妥布霉素组合，对革兰氏阴性病原体肺炎克雷伯氏菌(Klebsiella pneumoniae)、铜绿假单胞菌(Pseudomonasaeruginosa)和鲍曼不动杆菌(Acinetobacter baumannii)的多药和广泛耐药菌株表现出协同效应。
所有测试的菌株对主要类别的抗生素表现出抗性表型，所述抗生素包括喹诺酮类、氨基糖苷类和β-内酰胺类。所有菌株均为碳青霉烯酶(carbapenemase)生产者，其中肺炎克雷伯氏菌、铜绿假单胞菌和鲍曼不动杆菌菌株分别编码KPC-型酶、金属-β-内酰胺酶(VIM-1和IMP-13酶)和OXA-24酶。所有菌株属于成功的高风险克隆菌株，其已知在抗生素抗性传播中发挥重要作用[17]。
值得注意的是，所测试的组合被证明对粘菌素抗性菌株是成功的。考虑到粘菌素和SET-M33之前被假定具有相同作用机制，这更让人感到惊讶[10]。
因此，本发明的目的是提供抗菌肽KKIRVRLSA与选自美罗培南、利福平、氨曲南和妥布霉素的抗微生物剂的治疗组合，用于治疗由一种或多种下列细菌种类所引起的人类或动物感染：肺炎克雷伯氏菌、铜绿假单胞菌和鲍曼不动杆菌。
肽KKIRVRLSA可根据已知方法制备，例如Brunetti J等人，In vitro and in vivoefficacy，toxicity，bio-distribution and resistance selection of a novelantibacterial drug candidate.Sci Rep.2016；6：26077.doi：10.1038/srep26077中描述。所述肽可以以线性形式或以多聚体形式提供，例如以树枝状形式且尤其是双支化或四支化形式，或以多抗原肽形式，如EP2344178和WO2010/038220中所述。KKIRVRLSA肽中所含氨基酸残基可为L-或D-构型；EP2595496中描述了其中所有氨基酸均为D-构型的肽KKIRVRLSA。
在一个优选的实施方案中，肽M33或其类似物或衍生物与选自美罗培南和氨曲南的抗微生物剂组合，且所述组合用于治疗由细菌种类铜绿假单胞菌引起的感染。
在另一个优选的实施方案中，肽M33或其类似物或衍生物与选自美罗培南、氨曲南、妥布霉素和利福平的抗微生物剂组合，且所述组合用于治疗由细菌种类鲍曼不动杆菌引起的感染。
在进一步优选的实施方案中，肽M33或其类似物或衍生物与抗微生物剂利福平组合，且所述组合用于治疗由细菌种类肺炎克雷伯氏菌引起的感染。
为了确定对治疗感染个体最有效的肽M33和抗生素的组合，可测定来自所述个体的生物样本对本发明不同组合的响应性。因此，在另一个实施方案中，本发明提供如上定义的组合，用于治疗感染的方法，所述方法包括：
1)提供来自被诊断为感染阳性受试者的生物流体或组织，所述受试者被以下一种或多种细菌种类感染：肺炎克雷伯氏菌、铜绿假单胞菌和鲍曼不动杆菌；
2)在体外测试感染菌株对如前文定义的组合的响应性，
且，如果菌株生长在体外被所述组合抑制，
3)向受试者施用所述组合。
本发明进一步提供用于治疗由一种或多种选自肺炎克雷伯氏菌、铜绿假单胞菌和鲍曼不动杆菌的革兰氏阴性病原体所引起的感染的试剂盒，其中肽M33和一种或多种选自美罗培南、利福平、氨曲南和妥布霉素的抗生素与药学上可接受的载体和赋形剂一起被置于单独容器中，以合适形式提供用于同时或分别、例如相继施用于有需要的受试者。
本发明进一步提供含有肽SET-M33和一种或多种选自美罗培南、利福平、氨曲南和妥布霉素的抗生素药物及药学上可接受赋形剂的药物组合物。所述药物组合物适于口服、局部或胃肠外施用，且其优选为片剂、胶囊、可注射溶液、洗眼液、漱口剂、喷雾剂、气溶胶、霜剂或软膏形式。本发明药物组合物可根据标准方法配制，如Remington’sPharmaceuticals Sciences Handbook，Mack Pub.Co.，NY，USA，XVII ed中所述的那些。可用于配制本发明组合物的药学上可接受的赋形剂特别描述于Handbook ofPharmaceuticals Excipients，American Pharmaceutical Association(PharmaceuticalPress；第6修订版，2009)中。
根据本发明的试剂盒和药物组合物含有有效量的肽和抗生素药物。肽M33的合适每日用量范围为0.5mg/Kg至50mg/Kg，优选为3mg/Kg至15mg/Kg。抗生素药物的量通常在标准治疗区间内，且取决于所用的特定分子、疾病的严重程度和待治疗患者的一般情况，或可以基于患者对治疗的响应性进行评估。
以下实验部分进一步阐述了本发明。
实验部分
材料及方法
肽合成
使用Syro多肽合成仪(MultiSynTech，Witten，Germany)、通过标准Fmoc化学固相合成SET-M33。对R采用侧链保护基团2，2，4，6，7-五甲基二氢苯并呋喃-5-磺酰基，对K采用叔丁氧羰基，对S采用叔丁基(Iris Biotech GmbH，Marktredwitz，Germany)。将最终产物从固体载体上裂除，用TFA、含有三异丙基硅烷和水(95/2.5/2.5)处理而脱保护，并用乙醚沉淀。最终肽的纯度和鉴定通过Phenomenex Jupiter C18分析柱(250×4.6mm)反相色谱和质谱确认。
细菌菌株
在6个充分表征的临床菌株上评估SET-M33和抗生素的活性。菌株的选择依据其抗性表型和基因型。每种菌种的详细描述如表中所报告。
体外易感性试验
根据临床和实验室标准研究的指南、使用标准肉汤微量稀释测定法测定MIC[14]。
采用棋盘法[15]、使用阳离子调节的Mueller-Hinton肉汤(MHB)在96-孔微量滴定板(Sarstedt，Inc.，Newton，NC)中评价组合的抗微生物活性，六种菌株中的每一种均一式两份。采用5×104CFU/孔的最终细菌接种物、最终体积为100μl进行测定。在35℃孵育20小时后记录结果。每种抗生素组合的总的分数抑制浓度(∑FIC)依据EUCAST确定性文件E.Def1.2[16]如下计算：∑FIC等于试剂A的FIC与试剂B的FIC的加和，其中试剂A或B的FIC是在另一方存在时试剂A或B的MIC除以试剂A或B单独时的MIC值所得。根据以下定义解释结果：∑FIC≤0.5表示协同效应，1＞∑FIC＞0.5表示累加效应，2＞∑FIC＞1表示无差异(indifference)，且∑FIC≥2表示拮抗效应。
结果
SET-M33的MIC值在4和32μg/mL间变化，其它抗生素的MIC总是在抗性范围内，酌情依据EUCAST临床断点(clinical breakpoint)[19]。
SET-M33和美罗培南对六种菌株中的两种(铜绿假单胞菌和鲍曼不动杆菌)有协同效应，并对剩余菌株显示出累加效应。观察到SET-M33和利福平的组合对六种菌株中的三种有协同效应，包括肺炎克雷伯氏菌和鲍曼不动杆菌菌株。SET-M33和氨曲南对一种铜绿假单胞菌及两种鲍曼不动杆菌菌株表现出协同效应。当SET-M33和妥布霉素组合使用时，同样观察到对鲍曼不动杆菌株之一具有协同效应(见表格)。当SET-M33和环丙沙星组合使用时仅观察到累加效应(未标注)。值得注意的是，未检测到拮抗效应。
对导致生长抑制的抗生素组合的分析显示，在大多数情况下，SET-M33MIC值受到适度影响(当出现协同效应时，例如与利福平、氨曲南和妥布霉素组合)或不受影响(当效应为累加效应或无差异)。另一方面，常规抗生素的MIC值受到显著影响，在协同效应的情况下降至128分之一(例如美罗培南和利福平)(见表格)。
有趣的是，与利福平或氨曲南组合时，SET-M33甚至显示出对粘菌素抗性肺炎克雷伯氏菌株的协同活性。
参考文献：
[1]Rossolini GM，Arena F，Pecile P，Pollini S.Update on the antibioticresistance crisis.Curr Opin Pharmacol.2014；18：56-60.doi：10.1016/j.coph.2014.09.006.
[2]Viale P，Giannella M，Tedeschi S，Lewis R.Treatment of MDR-Gramnegative infections in the 21st century：a never ending threat forclinicians.Curr Opin Pharmacol.2015；24：30-7.doi：10.1016/j.coph.2015.07.001.
[3]Bassetti M，Righi E.New antibiotics and antimicrobial combinationtherapy for the treatment of gram-negative bacterial infections.Curr OpinCrit Care.2015；21(5)：402-11.doi：10.1097/MCC.0000000000000235.
[4]Pini A，Giuliani A，Falciani C，Runci Y，Ricci C，Lelli B，Malossi M，Neri P，Rossolini GM，Bracci L.Antimicrobial activity of novel dendrimericpeptides obtained by phage display selection and rationalmodification.Antimicrob Agents Chemother 2005，49：2665-72.
[5]Pini A，Falciani C，Mantengoli E，Bindi S，Brunetti J，Iozzi S，Rossolini GM，Bracci L.A novel tetrabranched antimicrobial peptide thatneutralizes bacterial lipopolysaccharide and prevents septic shock invivo.FASEB J 2010，24：1015-22.
[6]Pini A，Lozzi L，Bernini A，Brunetti J，Falciani C，Scali S，Bindi S，DiMaggio T，Rossolini GM，Niccolai N，Bracci L.Efficacy and toxicity of theantimicrobial peptide M33produced with different counter-ions.Amino Acids2012，43：467-73.
[7]Falciani C，Lozzi L，Scali S，Brunetti J，Bracci L，Pini A.Site-specific pegylation of an antimicrobial peptide increases resistance toPseudomonas aeruginosa elastase.Amino Acids 2014，46：1403-7.
[8]Pini A，Giuliani A，Falciani C，Fabbrini M，Pileri S，Lelli B，BracciL.Characterization of the branched antimicrobial peptide M6by analyzing itsmechanism of action and in vivo toxicity.J Pept Sci 2007，13：393-9
[9]Falciani C，Lozzi L，Pollini S，Luca V，Carnicelli V，Brunetti J，LelliB，Bindi S，Scali S，Di Giulio A，Rossolini GM，Mangoni ML，Bracci L，PiniA.Isomerization of an antimicrobial peptide broadens antimicrobial spectrumto Gram-positive bacterial pathogens.PLoS One 2012，7：e46259.
[10]Brunetti J，Falciani C，Roscia G，Pollini S，Bindi S，Scali S，ArrietaUC，Gómez-Vallejo V，Quercini L，Ibba E，Prato M，Rossolini GM，Llop J，Bracci L，Pini A.In vitro and in vivo efficacy，toxicity，bio-distribution and resistanceselection of a novel antibacterial drug candidate.Scientific Reports 2016，6：26077.
[11]Kalan L，Wright GD.2011.Antibiotic adjuvants：multicomponentantiinfective strategies.Expert Rev Mol Med 13：e5.doi：10.1017/S1462399410001766.
[12]Hu Y，Liu A，Vaudrey J，Vaiciunaite B，Moigboi C，McTavish SM，KearnsA，Coates A.2015.Combinations of β-lactam or aminoglycoside antibiotics withplectasin are synergistic against methicillin-sensitive and methicillin-resistant Staphylococcus aureus.PLoS One 10：e0117664.http://dx.doi.org/10.1371/journal，pone.0117664
[13]Soothill G，Hu Y，Coates A.Can we prevent antimicrobial resistanceby using antimicrobials better？Pathogens 2013；2：422-435.
[14]CLSI Methods for dilution antimicrobial susceptibility tests forbacteria that grow aerobically；Approved Standard-Tenth Edition.CLSI documentM07-A10.Wayne，PA(2015).
[15]Marques MB，Brookings ES，Moser SA，Sonke PB，Waites KB.Comparativein vitro antimicrobial susceptibilities of nosocomial isolates ofAcinetobacter baumannii and synergistic activities of nine antimicrobialcombinations.Antimicrob.Agents Chemother.1997；41：881-885.
[16]European Committee for Antimicrobial SusceptibilityTesting.2000.Terminology relating to methods for the determination ofsusceptibility of bacteria to antimicrobial agents.EUCAST definitive documentE.Def 1.2.，2000，EUCAST，Basel，Switzerland.
[17]Woodford N，Turton JF，Livermore DM.Multiresistant Gram-negativebacteria：the role of high-risk clones in the dissemination of antibioticresistance.FEMS Microbiol Rev.2011；35(5)：736-55.
[18]Fiel SB.Aerosolized antibiotics in cystic fibrosis：anupdate.Expert Rev Respir Med.2014；8(3)：305-14.doi：10.1586/17476348.2014.896205.
[19]EUCAST clinical breakpoint v.6.0，www.eucast，org/clinical_breakpoints，accessed November 2016.
[20]Soren O，Brinch KS，Patel D，Liu Y，Liu A，Coates A，Hu Y.Antimicrobialpeptide novicidin synergizes with rifampin，ceftriaxone，and ceftazidimeagainst antibiotic-resistant enterobacteriaceae in vitro.Antimicrob AgentsChemother.2015；59(10)：6233-40.doi：10.1128/AAC.01245-15.
[21]Tascini C，Tagliaferri E，Giani T，Leonildi A，Flammini S，Casini B，Lewis R，Ferranti S，Rossolini GM，Menichetti F.Synergistic activity of colistinplus rifampin against colistin-resistant KPC-producing Klebsiellapneumoniae.Antimicrob Agents Chemother.2013；57(8)：3990-3.doi：10.1128/AAC.00179-13.
[22]Zusman O，Avni T，Leibovici L，Adler A，Friberg L，Stergiopoulou T，Carmeli Y，Paul M.Systematic review and meta-analysis of in vitro synergy ofpolymyxins and carbapenems.Antimicrob Agents Chemother.2013；57(10)：5104-11.doi：10.1128/AAC.01230-13.
[23]Nastro M，Rodríguez CH，Monge R，Zintgraff J，Neira L，Rebollo M，VayC，Famiglietti A.Activity of the colistin-rifampicin combination againstcolistin-resistant，carbapenemase-producing Gram-negative bacteria.JChemother.2014；26(4)：211-6.doi：10.1179/1973947813Y.0000000136.
[24]Bae S，Kim MC，Park SJ，Kim HS，Sung H，Kim MN，Kim SH，Lee SO，Choi SH，Woo JH，Kim YS，Chong YP.In vitro synergistic activity of antimicrobial agentsin combination against clinical isolates of colistin-resistant Acinetobacterbaumannii.Antimicrob Agents Chemother.2016 Sep 6.pii：AAC.00839-16.
[25]Safarika A，Galani I，Pistiki A，Giamarellos-Bourboulis EJ.Time-killeffect of levofioxacin on multidrug-resistant Pseudomonas aeruginosa andAcinetobacter baumannii：synergism with imipenem and colistin.Eur J ClinMicrobiol Infect Dis.2015；34(2)：317-23.doi：10.1007/s10096-014-2231-7.
[26]T，Hickman RA，Forsberg P，P，Giske CG，CarsO.Evaluation of double-and triple-antibiotic combinations for VIM-and NDM-producing Klebsiella pneumoniae by in vitro time-kill experiments.AntimicrobAgents Chemother.2014；58(3)：1757-62.doi：10.1128/AAC.00741-13.
[27]Vaara M，Siikanen O，Apajalahti J，N，VaaraT.Susceptibility of carbapenemase-producing strains of Klebsiella pneumoniaeand Escherichia coli to the direct antibacterial activity of NAB739 and tothe synergistic activity of NAB7061 with rifampicin and clarithromycin.JAntimicrob Chemother.2010；65(5)：942-5.doi：10.1093/jac/dkq040.
[28]Zhou Y，Peng Y.Synergistic effect of clinically used antibioticsand peptide antibiotics against Gram-positive and Gram-negative bacteria.ExpTher Med.2013；6(4)：1000-1004.
[29]Bozkurt-Guzel C，Savage PB，Gerceker AA.In vitro activities of thenovel ceragenin CSA-13，alone or in combination with colistin，tobramycin，andciprofloxacin，against Pseudomonas aeruginosa strains isolated from cysticfibrosis patients.Chemotherapy.2011；57(6)：505-10.doi：10.1159/000335588.
[30]Zhang Y，Liu Y，Sun Y，Liu Q，Wang X，Li Z，Hao J.In vitro synergisticactivities of antimicrobial peptide brevinin-2CE with five kinds ofantibiotics against multidrug-resistant clinical isolates.CurrMicrobiol.2014；68(6)：685-92.doi：10.1007/s00284-014-0529-4.
[31]He J，Starr CG，Wimley WC.A lack of synergy between membrane-permeabilizing cationic antimicrobial peptides and conventionalantibiotics.Biochim Biophys Acta.2015；1848(1 Pt A)：8-15.doi：10.1016/j.bbamem.2014.09.010.
[32]Brunetti J，Roscia G，Lampronti I，Gambari R，Quercini L，Falciani C，Bracci L，Pini A.Immunomodulatory and anti-inflammatory activity in vitro andin vivo of a novel antimicrobial candidate.J Biol Chem.2016 Oct 7.pii：jbc.M116.750257.
[33]Magiorakos AP，Srinivasan A，Carey RB，Carmeli Y，Falagas ME，GiskeCG，Harbarth S，Hindler JF，Kahlmeter G，Olsson-Liljequist B，Paterson DL，Rice LB，Stelling J，Struelens MJ，Vatopoulos A，Weber JT，Monnet DL.Multidrug-resistant，extensively drug-resistant and pandrug-resistant bacteria：an internationalexpert proposal for interim standard definitions for acquired resistance.ClinMicrobiol Infect.2012；18(3)：268-81.doi：10.1111/j.1469-0691.2011.03570.x。

Claims (13)

1.抗菌肽KKIRVRLSA(SEQ ID NO：1)、其类似物或衍生物与选自美罗培南、利福平、氨曲南和妥布霉素的抗微生物剂的组合，用于治疗由一种或多种以下细菌种类所引起的人类或动物感染：肺炎克雷伯氏菌、铜绿假单胞菌和鲍曼不动杆菌。
2.根据权利要求1使用的组合，其中的抗微生物剂选自美罗培南和氨曲南，且所述细菌种类是铜绿假单胞菌。
3.根据权利要求1使用的组合，其中的抗微生物剂选自美罗培南、氨曲南、妥布霉素和利福平，且所述细菌种类是鲍曼不动杆菌。
4.根据权利要求1使用的组合，其中的抗微生物剂是利福平且所述细菌种类是肺炎克雷伯氏菌。
5.抗菌肽KKIRVRLSA(SEQ ID NO：1)、其类似物或衍生物与选自美罗培南、利福平、氨曲南和妥布霉素的抗微生物剂的组合，用于治疗感染的方法，所述方法包括：
a)提供来自被诊断为感染阳性的受试者的生物流体或组织样品，所述受试者被以下一种或多种细菌种类感染：肺炎克雷伯氏菌、铜绿假单胞菌和鲍曼不动杆菌；
b)在体外测试感染菌株对以上定义的组合的响应性，和
c)如果所述菌株生长在体外被所述组合抑制，就向受试者施用所述组合。
6.根据权利要求1-5使用的组合，其中所述抗菌肽SEQ ID NO：1是线性形式或树枝状形式，尤其是双支化或四支化形式。
7.根据权利要求1-6使用的组合，其中SEQ ID NO：1的所有氨基酸是L-或D-构型。
8.根据权利要求1-7使用的组合，其中所述感染由所述细菌种类的多药抗性菌株或广泛药物抗性菌株引起。
9.试剂盒，其在分开的容器中含有抗菌肽SEQ ID NO：1、其类似物或衍生物和选自美罗培南、利福平、氨曲南和妥布霉素的抗微生物剂，用于治疗由一种或多种以下细菌种类引起的人类或动物感染的方法：肺炎克雷伯氏菌、铜绿假单胞菌和鲍曼不动杆菌，其中所述肽和抗微生物剂为同时或分别施用于有需要的受试者。
10.药物组合物，包含抗菌肽SEQ ID NO：1、其类似物或衍生物和选自美罗培南、利福平、氨曲南和妥布霉素的抗微生物剂，以及药学上可接受的赋形剂。
11.根据权利要求10的药物组合物，其为适于口服、胃肠外、气溶胶或局部施用的形式。
12.根据权利要求11的药物组合物，其为片剂、胶囊、可注射溶液、洗眼液、漱口剂、喷雾剂、气溶胶、霜剂或软膏形式。
13.根据权利要求9的试剂盒或根据权利要求10-12的药物组合物，其中的抗菌肽以剂量单位给予，其提供其日用量范围是0.5mg/kg至50mg/Kg，优选3mg/Kg至15mg/Kg。
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US11174288B2 (en) 2016-12-06 2021-11-16 Northeastern University Heparin-binding cationic peptide self-assembling peptide amphiphiles useful against drug-resistant bacteria
US10413584B1 (en) * 2018-08-29 2019-09-17 Riptide Bioscience, Inc. Peptides having immunomodulatory properties
US10548944B1 (en) 2018-10-19 2020-02-04 Riptide Bioscience, Inc. Antimicrobial peptides and methods of using the same
CN111057134B (zh) * 2019-12-17 2023-05-09 倪京满 一类具有广谱抗菌活性、低毒性且无诱导耐药性的抗菌肽及其应用
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4452778A (en) * 1980-03-31 1984-06-05 Eli Lilly And Company Synergistic antibacterial compositions and method of treatment of infections caused by multiple antibiotic-resistant organisms
US20110166119A1 (en) * 2008-12-01 2011-07-07 Glade Organics Private Limited Synergistic Combinations of Aztreonam with the Carbapenems Meropenem and Ertapenem
US20130130969A1 (en) * 2010-07-23 2013-05-23 Setlance S.R.L. Antimicrobial peptide, branched forms thereof and their use in the treatment of bacteria infections

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7214364B2 (en) * 2000-12-27 2007-05-08 Corus Pharma, Inc. Inhalable aztreonam lysinate formulation for treatment and prevention of pulmonary bacterial infections
US7738563B2 (en) 2004-07-08 2010-06-15 Freescale Semiconductor, Inc. Method and system for performing deblocking filtering
ITRM20040349A1 (it) 2004-07-13 2004-10-13 Univ Siena Peptidi antibatterici e loro analoghi.
JP5773271B2 (ja) 2008-10-05 2015-09-02 ウニヴェルシタ・デグリ・ストゥディ・ディ・シエナ 抗菌適用のためのペプチド配列、それらの分岐形態、及びその使用
CA2888068A1 (en) * 2014-04-15 2015-10-15 The Hospital For Sick Children Cationic antimicrobial peptides

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4452778A (en) * 1980-03-31 1984-06-05 Eli Lilly And Company Synergistic antibacterial compositions and method of treatment of infections caused by multiple antibiotic-resistant organisms
US20110166119A1 (en) * 2008-12-01 2011-07-07 Glade Organics Private Limited Synergistic Combinations of Aztreonam with the Carbapenems Meropenem and Ertapenem
US20130130969A1 (en) * 2010-07-23 2013-05-23 Setlance S.R.L. Antimicrobial peptide, branched forms thereof and their use in the treatment of bacteria infections

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CARL等: "In Vitro Double and Triple Bactericidal Activities of Doripenem, Polymyxin B, and Rifampin against Multidrug-Resistant Acinetobacter baumannii, Pseudomonas aeruginosa,Klebsiella pneumoniae, and Escherichia coli", 《ANTIMICROBIAL AGENTS AND CHEMOTHERAPY》 *
PINI等: "A novel tetrabranched antimicrobial peptide that neutralizes bacterial lipopolysaccharide and prevents septic shock in vivo", 《THE FASEB JOURNAL》 *

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