药学学报, 2021, 56(4): 1006-1015
引用本文:
李雪瑶, 李吉顺, 朱子豪, 李陶汀月, 张文轩, 夏杰, 李天磊, 吴松. 人用截短侧耳素类新药Lefamulin的研究进展[J]. 药学学报, 2021, 56(4): 1006-1015.
LI Xue-yao, LI Ji-shun, ZHU Zi-hao, LI Tao-ting-yue, ZHANG Wen-xuan, XIA Jie, LI Tian-lei, WU Song. Advances of Lefamulin: a new pleuromutilin antibiotic[J]. Acta Pharmaceutica Sinica, 2021, 56(4): 1006-1015.

人用截短侧耳素类新药Lefamulin的研究进展
李雪瑶1, 李吉顺1,3, 朱子豪1, 李陶汀月2, 张文轩1, 夏杰1, 李天磊1*, 吴松1*
1. 中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050;
2. 北京市一六一中学, 北京 100020;
3. 贵州中医药大学, 贵州 贵阳 550001
摘要:
Lefamulin(BC-3781)是第一个治疗系统性细菌感染的截短侧耳素类人用药物,属于半合成抗生素。在2019年8月由美国FDA批准用于治疗社区获得性细菌性肺炎(community-acquired bacterial pneumonia,CABP),商品名为Xenleta。Lefamulin通过与细菌核糖体50S亚基的肽基转移酶中心结合,阻断了肽基转移过程进而抑制了蛋白质合成。Lefamulin具有广泛的抗革兰阳性细菌活性,同时对CABP相关的非典型微生物(肺炎支原体)也具有较强的抗菌活性。本文针对截短侧耳素类新药Lefamulin的作用机制、抗菌谱、临床前和临床试验数据等四个方面进行综述。
关键词:    截短侧耳素      Lefamulin      抗菌活性      社区获得性肺炎     
Advances of Lefamulin: a new pleuromutilin antibiotic
LI Xue-yao1, LI Ji-shun1,3, ZHU Zi-hao1, LI Tao-ting-yue2, ZHANG Wen-xuan1, XIA Jie1, LI Tian-lei1*, WU Song1*
1. State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medical, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China;
2. Beijing No. 161 High School, Beijing 100020, China;
3. Guizhou University of Traditional Chinese Medicine, Guiyang 550001, China
Abstract:
Lefamulin (BC-3781) is a semi-synthetic pleuromutilin antibiotic, approved for the treatment of community-acquired bacterial pneumonia (CABP) by Food and Drug Administration (USA) in August 2019, with the commodity name of Xenleta. It is the first pleuromutilin antibiotics used for systemic treatment of bacterial infections in human. Lefamulin binds to the peptidyl transferase center of the 50S ribosomal subunit to prevent peptide transfer, thus inhibits protein synthesis. Lefamulin displays expanded activity against gram-positive organisms, and also shows high activity against atypical microorganism like Mycoplasma pneumoniae. This review discusses the mechanism, bacterial spectrum of activity, preclinical and clinical data of Lefamulin.
Key words:    pleuromutilin    Lefamulin    antibacterial activity    community-acquired bacterial pneumonia   
收稿日期: 2020-10-16
DOI: 10.16438/j.0513-4870.2020-1617
基金项目: 国家自然科学基金项目(81703364);中国医学科学院医学与健康科技创新工程重大协同创新项目(2017-I2M-1-011);北京市基础教育阶段创新人才培养项目——2019年第十一批翱翔计划.
通讯作者: 李天磊,Tel:86-10-83163542,E-mail:litianlei@imm.ac.cn;吴松,E-mail:ws@imm.ac.cn
Email: litianlei@imm.ac.cn;ws@imm.ac.cn
相关功能
PDF(1047KB) Free
打印本文
0
作者相关文章
李雪瑶  在本刊中的所有文章
李吉顺  在本刊中的所有文章
朱子豪  在本刊中的所有文章
李陶汀月  在本刊中的所有文章
张文轩  在本刊中的所有文章
夏杰  在本刊中的所有文章
李天磊  在本刊中的所有文章
吴松  在本刊中的所有文章

参考文献:
[1] Levy SB, Marshall B. Antibacterial resistance worldwide:causes, challenges and responses[J]. Nat Med, 2004, 10:S122-S129.
[2] Zhu YG, Johnson TA, Su JQ, et al. Diverse and abundant antibiotic resistance genes in Chinese swine farms[J]. Proc Natl Acad Sci U S A, 2013, 110:3435-3440.
[3] Veve MP, Wagner JL. Lefamulin:review of a promising novel pleuromutilin antibiotic[J]. Pharmacotherapy, 2018, 38:935-946.
[4] Daum RS, Kar S, Kirkpatrick P. Retapamulin[J]. Nat Rev Drug Discov, 2007, 6:865-866.
[5] Kavanagh F, Hervey A, Robbins WJ. Antibiotic substances from basidiomycetes:VⅢ. Pleurotus multilus (Fr.) Sacc. and Pleurotus passeckerianus Pilat[J]. Proc Natl Acad Sci U S A, 1951, 37:570-574.
[6] Goethe O, Heuer A, Ma X, et al. Antibacterial properties and clinical potential of pleuromutilins[J]. Nat Prod Rep, 2019, 36:220-247.
[7] Hunt E. Pleuromutilin antibiotics[J]. Drugs Future, 2000, 25:1163-1168.
[8] Lefamulin evaluation against pneumonia (LEAP2Phase) 3 topline Results[EB/OL]. https://investors.nabriva.com/static-files/5c34b447-99cc-4739-b9d6-d4ea4c7d13b9.
[9] Poehlsgaard J, Douthwaite S. The bacterial ribosome as a target for antibiotics[J]. Nat Rev Microbiol, 2005, 3:870-881.
[10] Merk A, Bartesaghi A, Banerjee S, et al. Breaking cryo-EM resolution barriers to facilitate drug discovery[J]. Cell, 2016, 165:1698-1707.
[11] Eyal Z, Matzov D, Krupkin M, et al. A novel pleuromutilin antibacterial compound, its binding mode and selectivity mechanism[J]. Sci Rep, 2016, 6:39004.
[12] Poulsen SM, Karlsson M, Johansson LB, et al. The pleuromutilin drugs tiamulin and valnemulin bind to the RNA at the peptidyl transferase centre on the ribosome[J]. Mol Microbiol, 2001, 41:1091-1099.
[13] Paukner S, Sader HS, Ivezic-Schoenfeld Z, et al. Antimicrobial activity of the pleuromutilin antibiotic BC-3781 against bacterial pathogens isolated in the SENTRY antimicrobial surveillance program in 2010[J]. Antimicrob Agents Chemother, 2013, 57:4489-4495.
[14] Sader HS, Paukner S, Ivezic-Schoenfeld Z, et al. Antimicrobial activity of the novel pleuromutilin antibiotic BC-3781 against organisms responsible for community-acquired respiratory tract infections (CARTIs)[J]. J Antimicrob Chemother, 2012, 67:1170-1175.
[15] Mendes RE, Farrell DJ, Flamm RK, et al. In vitro activity of lefamulin tested against Streptococcus pneumoniae with defined serotypes, including multidrug-resistant isolates causing lower respiratory tract infections in the United States[J]. Antimicrob Agents Chemother, 2016, 60:4407-4411.
[16] Paukner S, Gelone SP, Arends SJR, et al. Antibacterial activity of lefamulin against pathogens most commonly causing community-acquired bacterial pneumonia:SENTRY Antimicrobial Surveillance Program (2015-2016)[J]. Antimicrob Agents Chemother, 2019, 63:e02161-18.
[17] Knöppel A, Näsvall J, Andersson DI. Evolution of antibiotic resistance without antibiotic exposure[J]. Antimicrob Agents Chemother, 2017, 61:e01495-17.
[18] Butler MM, Waidyarachchi SL, Connolly KL, et al. Aminomethyl spectinomycins as therapeutics for drug-resistant gonorrhea and chlamydia coinfections[J]. Antimicrob Agents Chemother, 2018, 62:e00325-18.
[19] Mendes RE, Doyle TB, Paukner S, et al. Molecular characterization of resistance mechanisms associated with pleuromutilins among gram-positive clinical isolates from the worldwide SENTRY surveillance studies for lefamulin[EB/OL]. https://www.nabriva.com/Portals/0/Assets/ASM_Microbe_SENTRY%2020152016%20resistance%20mechanisms_P642.pdf.
[20] Wicha WW, Ivezic-Schoenfeld Z, Novak R. Pharmacokinetic, mass balance and tissue distribution of[14C]-BC-3781 in non-pigmented rats[EB/OL]. https://www.nabriva.com/Portals/0/Nabriva/Posters/ECCMID_2010/2010%20ECCMID_Nabriva%20poster%20909_abstract%202415_ADME%20BC-3781.pdf.
[21] Wicha WW, Paukner S, Strickmann DB, et al. Pharmacokinetics-pharmacodynamics of lefamulin in a neutropenic murine lung infection model[EB/OL]. https://www.nabriva.com/Portals/_default/Skins/ProfessionalUs/pdfs/2015%20pharmacokinetics-pharmacodynamics-lefamulin-in-lung-infection.pdf.
[22] Wicha WW, Kappes CB, Fischer E. Efficacy of lefamulin against Staphylococcus aureus induced bacteremia in a neutropenic and immunocompetent murine model[EB/OL]. https://www.nabriva.com/Portals/_default/Skins/ProfessionalUs/pdfs/Poster_1509_ID%20Week%202017_Vivo%20Bacteremia_Final.pdf.
[23] Wicha WW, Henson C, Webbley K. Tissue distribution of[14C]-Lefamulin in the urogenital tract in rats[EB/OL]. https://www.nabriva.com/Portals/0/Nabriva/Posters/ECCMID_2018/ECCMID%202018%20QWBA-STI_Final.pdf.
[24] Zeitlinger M, Schwameis R, Burian A, et al. Simultaneous assessment of the pharmacokinetics of a pleuromutilin, lefamulin, in plasma, soft tissues and pulmonary epithelial lining fluid[J]. J Antimicrob Chemother, 2016, 71:1022-1026.
[25] Wicha WW, Lell C, Seltzer E, et al. Pharmacokinetics and safety of an oral, immediate-release (IR) tablet formulation of lefamulin in fed and fasted healthy subjects[EB/OL]. https://www.nabriva.com/Portals/_default/Skins/ProfessionalUs/pdfs/2017-%20pharmacokinetics-immediate-release-tablet-%20p1336-be-study.pdf.
[26] A Study to assess mass balance recovery,metabolite profile and identification of IV and oral 14C-BC-3781[EB/OL]. https://www.clinicaltrials.gov/ct2/show/NCT03131141?term=lefamulin&draw=2&rank=4.
[27] Cates JE, Mitrani-Gold FS, Li G, et al. Systematic review and meta-analysis to estimate antibacterial treatment effect in acute bacterial skin and skin structure infection[J]. Antimicrob Agents Chemother, 2015, 59:4510-4520.
[28] Prince WT, Ivezic-Schoenfeld Z, Lell C, et al. Phase Ⅱ clinical study of BC-3781, a pleuromutilin antibiotic, in treatment of patients with acute bacterial skin and skin structure infections[J]. Antimicrob Agents Chemother, 2013, 57:2087-2094.
[29] Rubino CM, Xue B, Bhavnani SM, et al. Population pharmacokinetic analyses for BC-3781 using phase 2 data from patients with acute bacterial skin and skin structure infections[J]. Antimicrob Agents Chemother, 2015, 59:282-288.
[30] File TM, Goldberg L, Das A, et al. Efficacy and safety of intravenous-to-oral lefamulin, a pleuromutilin antibiotic, for the treatment of community-acquired bacterial pneumonia:the phase Ⅲ lefamulin evaluation against pneumonia (LEAP 1) trial[J]. Clin Infect Dis, 2019, 69:1856-1867.
[31] Alexander E, Goldberg L, Das AF, et al. Oral lefamulin vs moxifloxacin for early clinical response among adults with community-acquired bacterial pneumonia:the LEAP 2 randomized clinical trial[J]. JAMA, 2019, 322:1661-1671.
[32] Theuretzbacher U, Bush K, Harbarth S, et al. Critical analysis of antibacterial agents in clinical development[J]. Nat Rev Microbiol, 2020, 18:286-298.
相关文献:
1.王新杨, 陈敏, 王铎, 陈向东, 凌勇, 王晓丽, 汪辉.新型截短侧耳素衍生物的合成及抗菌活性研究[J]. 药学学报, 2015,50(10): 1297-1304