一种不易诱发耐药性的新型抗生素teixobactin的研究进展
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摘要
细菌耐药问题已经成为21世纪世界上最大的健康问题之一。发现新抗生素的速度越来越慢以及新耐药细菌的产生加速了新抗生素的需求。来源于难培养土壤微生物的缩肽类抗生素teixobactin具有独特新颖的抗菌机制,即和细菌细胞壁上肽聚糖前体脂质Ⅱ及壁磷壁酸前体脂质Ⅲ的保守序列结合,以致细菌细胞壁不能合成,可以杀死多种耐药性致病菌,包括耐甲氧西林金黄色葡萄球菌(methicillin-resistant Staphylococcus aureus, MRSA)和结核分枝杆菌(Mycobacterium tuberculosis)等。这种特殊的作用方式使病原体对其很难产生耐药性,因此,teixobactin被认为是"明星抗生素"。自teixobactin发现以来,它的生物活性、作用机制、构效关系等逐步被揭示,其化学全合成也得以实现,但是生物合成的研究相对滞后。本文总结了近几年来有关teixobactin的研究进展,讨论了其不易诱发耐药性的机制,并展望了其在生物合成方面的研究。
Bacterial resistance to existing drugs, a growing public concern worldwide, poses a threat to the health of humans. As the discovery of new antimicrobial drugs becomes extremely difficult and massive bacterial resistance emerges, it is urgent to search for new antibiotics. Teixobactin, a depsipeptide discovered in a screen of uncultured bacteria, inhibits cell wall synthesis by binding to a highly conserved motif of lipid Ⅱ(precursor of peptidoglycan) and lipid Ⅲ(precursor of cell wall teichoic acid) and kills a variety of drug-resistant pathogens, including clinically resistant bacteria such as methicillin-resistant Staphylococcus aureus(MRSA) and Mycobaterium tuberculosis. Remarkably, since no teixobactin-resistant bacterial strains have been obtained due to its novel modes of action to kill pathogens, teixobactin has been considered to be a "star antibiotic". Since the discovery of teixobactin in 2015, its biological activity, modes of action, and structure-activity relationship(SAR) have been gradually revealed, and its total chemical synthesis has also been achieved, while the research on biosynthesis falls behind. This article summarizes the research progress of teixobactin in recent years, discusses the modes of actions that helps it kill pathogens without resistance development, and looks forward to the research on its biosynthesis.
Bacterial resistance to existing drugs, a growing public concern worldwide, poses a threat to the health of humans. As the discovery of new antimicrobial drugs becomes extremely difficult and massive bacterial resistance emerges, it is urgent to search for new antibiotics. Teixobactin, a depsipeptide discovered in a screen of uncultured bacteria, inhibits cell wall synthesis by binding to a highly conserved motif of lipid Ⅱ(precursor of peptidoglycan) and lipid Ⅲ(precursor of cell wall teichoic acid) and kills a variety of drug-resistant pathogens, including clinically resistant bacteria such as methicillin-resistant Staphylococcus aureus(MRSA) and Mycobaterium tuberculosis. Remarkably, since no teixobactin-resistant bacterial strains have been obtained due to its novel modes of action to kill pathogens, teixobactin has been considered to be a "star antibiotic". Since the discovery of teixobactin in 2015, its biological activity, modes of action, and structure-activity relationship(SAR) have been gradually revealed, and its total chemical synthesis has also been achieved, while the research on biosynthesis falls behind. This article summarizes the research progress of teixobactin in recent years, discusses the modes of actions that helps it kill pathogens without resistance development, and looks forward to the research on its biosynthesis.
引文
[1]Bush K,Courvalin P,Dantas G,et al.Tackling antibiotic resistance[J].Nat Rev Microbiol,2011,9(12):894-896.
[2]Sch?berle T F,Hack I M.Overcoming the current deadlock in antibiotic research[J].Trends Microbiol,2014,22(4):165-167.
[3]Nichols D,Cahoon N,Trakhtenberg E M,et al.Use of iChip for high-throughput in situ cultivation of"uncultivable"microbial species[J].Appl Environ Microbiol,2010,76(8):2445-2450.
[4]Ling L L,Schneider T,Peoples A J,et al.A new antibiotic kills pathogens without detectable resistance[J].Nature,2015,520(7547):455-459.
[5]Homma T,Nuxoll A,Gandt A B,et al.Dual Targeting of cell wall precursors by teixobactin leads to cell lysis[J].Antimicrob Agents Ch,2016,60(11):6510-6517.
[6]Wright G.Antibiotics:An irresistible newcomer[J].Nature,2015,517(7535):442-444.
[7]Arias C A,Murray B E.A new antibiotic and the evolution of resistance[J].New Engl J Med,2015,372(12):1168-1170.
[8]Jin K,Po K H L,Wang S,et al.Synthesis and structureactivity relationship of teixobactin analogues via convergent Ser ligation[J].Bioorgan Med Chem,2017,25(18):4990-4995.
[9]Magarvey N A,Haltli B,He M,et al.Biosynthetic pathway for mannopeptimycins,lipoglycopeptide antibiotics active against drug-resistant gram-positive pathogens[J].Antimicrob Agents Ch,2006,50(6):2167-2177.
[10]Yin X,Zabriskie T M.The enduracidin biosynthetic gene cluster from Streptomyces fungicidicus[J].Microbiology,2006,152(Pt10):2969-2983.
[11]Hatano K,Nogami I,Higashide E,et al.Biosynthesis of enduracidin:Origin of enduracididine and other amino acids[J].B Chem Soc Jpn,1984,48(6):1503-1508.
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[13]Han L,Schwabacher A W,Moran G R,et al.Streptomyces wadayamensis MppP is a pyridoxal 5'-phosphatedependent L-arginineα-deaminase,γ-hydroxylase in the enduracididine biosynthetic pathway[J].Biochemistry,2015,54(47):7029-7040.
[14]Burroughs A M,Hoppe R W,Goebel N C,et al.Structural and functional characterization of MppR,an enduracididine biosynthetic enzyme from Streptomyces hygroscopicus:functional diversity in the acetoacetate decarboxylase-like superfamily[J].Biochemistry,2013,52(26):4492-4506.
[15]Rudolph J,Hannig F,Theis H,et al.Highly efficient chiralpool synthesis of(2S,4R)-4-hydroxyornithine[J].Org Lett,2001,3(20):3153-3155.
[16]Craig W,Chen J,Richardson D,et al.A highly stereoselective and scalable synthesis of L-allo-enduracididine[J].Org Lett,2015,17(18):4620.
[17]Giltrap A M,Dowman L J,Nagalingam G,et al.Total synthesis of teixobactin[J].Org Lett,2016.18(11):2788-2791.
[18]Dhara S,Gunjal V B,Handore K L,et al.Solution-phase synthesis of the macrocyclic core of teixobactin[J].Eur JOrg Chem,2016,2016(25):4289-4293.
[19]Breukink E,de Kruijff B.Lipid II as a target for antibiotics[J].Nat Rev Drug discov,2006,5(4):321-332.
[20]Xing B,Jiang T,Wu X,et al.Molecular interactions between glycopeptide vancomycin and bacterial cell wall peptide analogues[J].Chemistry,2011,17(50):14170-14177.
[21]Loll P J,Derhovanessian A,Shapovalov M V,et al.Vancomycin forms ligand-mediated supramolecular complexes[J].J Mol Biol,2009,385(1):200-211.
[22]Xie J,Pierce J G,James R C,et al.A redesigned vancomycin engineered for dual D-Ala-D-ala And D-AlaD-Lac binding exhibits potent antimicrobial activity against vancomycin-resistant bacteria[J].J Am Chem Soc,2011,133(35):13946-139469.
[23]Wiedemann I,Breukink E,van Kraaij C,et al.Specific binding of nisin to the peptidoglycan precursor lipid II combines pore formation and inhibition of cell wall biosynthesis for potent antibiotic activity[J].J Biol Chem,2001,276(3):1772-1779.
[24]Hover B M,Kim S H,Katz M,et al.Culture-independent discovery of the malacidins as calcium-dependent antibiotics with activity against multidrug-resistant Gram-positive pathogens[J].Nat Microbiol,(2018)12 February 2018,doi:10.1038/s41564-018-0110-1.
[25]D'Elia M A,Pereira M P,Chung Y S,et al.Lesions in teichoic acid biosynthesis in Staphylococcus aureus lead to a lethal gain of function in the otherwise dispensable pathway[J].J Bacteriol,2006,188(12):4183-4189.
[26]Bierbaum G,Sahl H G.Induction of autolysis of staphylococci by the basic peptide antibiotics Pep 5and nisin and their influence on the activity of autolytic enzymes[J].Arch Microbiol,1985,141(3):249-254.
[27]Liu Y,Liu Y,Chan-Park M B,et al.Binding modes of teixobactin to lipid II:Molecular dynamics study[J].Sci Rep,2017,7(1):17197-17209.
[28]Guo C,Mandalapu D,Ji X,et al.Chemistry and biology of teixobactin.[J].Chemistry,(2017),12,doi:10.1002/chem.201704167.
[29]Jin K,Sam I H,Po K H,et al.Total synthesis of teixobactin[J].Nat Commun,2016,7(11):12394-12399.
[30]Jad Y E,Acosta G A,Naicker T,et al.Synthesis and biological evaluation of a teixobactin analogue[J].Org Lett,2015,17(24):6182-6185.
[31]Parmar A,Iyer A,Vincent C S,et al.Efficient total syntheses and biological activities of two teixobactin analogues[J].Chem Commun,2016,52(36):6060-6063.
[32]Yang H,Chen K H,Nowick J S.Elucidation of the teixobactin pharmacophore[J].ACS Chem Biol,2016,11(7):1823-1826.
[33]Jin K,Po K H L,Wang S,et al.Synthesis and structureactivity relationship of teixobactin analogues via convergent Ser ligation[J].Bioorgan Med Chem,2017,25(18):4990-4995.
[34]Parmar A,Iyer A,Lloyd D G,et al.Syntheses of potent teixobactin analogues against methicillin-resistant Staphylococcus aureus(MRSA)through the replacement of L-allo-enduracididine with its isosteres[J].Chem Commun,2017,53(55):7788-7791.
[35]Parmar A,Lyer A,Prior S H,et al.Teixobactin analogues reveal enduracididine to be non-essential for highly potent antibacterial activity and lipid II binding[J].Chem Sci,2017,8(12):8183-8192.
[36]Parmar A,Prior S H,Iyer A,et al.Defining the molecular structure of teixobactin analogues and understanding their role in antibacterial activities[J].Chem Commun,2017,53(12):2016-2019.
[37]Monaim S A H A,Jad Y E,Acosta G A,et al.Re-evaluation of the N-terminal substitution and the D-residues of teixobactin[J].RSC Adv,2016,6(77):73827-73829.
[38]Monaim S A H A,Jad Y E,Ramchuran E J,et al.Lysine scanning of Arg10-teixobactin:deciphering the role of hydrophobic and hydrophilic residues[J].ACS Omega,2016,1(6):1262-1265.
[39]Chen K H,Le S P,Han X,et al.Alanine scan reveals modifiable residues in teixobactin[J].Chem Commun,2017,53(82):11357-11359.
[40]Yang H,DuBois D R,Ziller J W,et al.X-ray crystallographic structure of a teixobactin analogue reveals key interactions of the teixobactin pharmacophore[J].Chem Commun,2017,53(18):2772-2775.
[41]Abdel Monaim S A H,Ramchuran E J,El-Faham A,et al.Converting teixobactin into a cationic antimicrobial peptide(AMP)[J].J Med Chem,2017,60(17):7476-7482.
[42]Monaim S A H A,Noki S,Ramchuran E J,et al.Investigation of the N-terminus amino function of Arg10-teixobactin[J].Molecules,2017,22(10):1632-1638.
[43]Parmar A,Lakshminarayanan R,Iyer A,et al.Design and syntheses of highly potent teixobactin analogues against Staphylococcus aureus,methicillin-resistant Staphylococcus aureus(MRSA),vancomycin-resistant enterococci(VRE)in vitro and in vivo[J].J Med Chem,2018,61(5):2009-2017.
[44]Mandalapu D,Ji X,Chen J,et al.Thioesterase-mediated synthesis of teixobactin analogues:Mechanism and substrate specificity[J].J Org Chem,2018,1,doi:10.1021/acs.joc.7b02462.
[45]Zhang Y,Buchholz F,Muyrers J P,et al.A new logic for DNA engineering using recombination in Escherichia coli[J].Nat Genet,1998,20(2):123-128.
[46]Fu J,Bian X,Hu S,et al.Full-length RecE enhances linearlinear homologous recombination and facilitates direct cloning for bioprospecting[J].Nat Biotechnol,2012,30(5):440-446.
[47]Wang H,Li Z,Jia R,et al.RecET direct cloning and Redαβrecombineering of biosynthetic gene clusters,large operons or single genes for heterologous expression[J].Nat Prot,2016,11(7):1175-1190.
[48]Wang H,Li Z,Jia R,et al.ExoCET:exonuclease in vitro assembly combined with RecET recombination for highly efficient direct DNA cloning from complex genomes[J].Nucleic Acids Res,2017,46(5):2697-2707.
[2]Sch?berle T F,Hack I M.Overcoming the current deadlock in antibiotic research[J].Trends Microbiol,2014,22(4):165-167.
[3]Nichols D,Cahoon N,Trakhtenberg E M,et al.Use of iChip for high-throughput in situ cultivation of"uncultivable"microbial species[J].Appl Environ Microbiol,2010,76(8):2445-2450.
[4]Ling L L,Schneider T,Peoples A J,et al.A new antibiotic kills pathogens without detectable resistance[J].Nature,2015,520(7547):455-459.
[5]Homma T,Nuxoll A,Gandt A B,et al.Dual Targeting of cell wall precursors by teixobactin leads to cell lysis[J].Antimicrob Agents Ch,2016,60(11):6510-6517.
[6]Wright G.Antibiotics:An irresistible newcomer[J].Nature,2015,517(7535):442-444.
[7]Arias C A,Murray B E.A new antibiotic and the evolution of resistance[J].New Engl J Med,2015,372(12):1168-1170.
[8]Jin K,Po K H L,Wang S,et al.Synthesis and structureactivity relationship of teixobactin analogues via convergent Ser ligation[J].Bioorgan Med Chem,2017,25(18):4990-4995.
[9]Magarvey N A,Haltli B,He M,et al.Biosynthetic pathway for mannopeptimycins,lipoglycopeptide antibiotics active against drug-resistant gram-positive pathogens[J].Antimicrob Agents Ch,2006,50(6):2167-2177.
[10]Yin X,Zabriskie T M.The enduracidin biosynthetic gene cluster from Streptomyces fungicidicus[J].Microbiology,2006,152(Pt10):2969-2983.
[11]Hatano K,Nogami I,Higashide E,et al.Biosynthesis of enduracidin:Origin of enduracididine and other amino acids[J].B Chem Soc Jpn,1984,48(6):1503-1508.
[12]Atkinson D J,Naysmith B J,Furkert D P,et al.Enduracididine,a rare amino acid component of peptide antibiotics:Natural products and synthesis[J].Beilstein JOrg Chem,2016,12(1):2325-2342.
[13]Han L,Schwabacher A W,Moran G R,et al.Streptomyces wadayamensis MppP is a pyridoxal 5'-phosphatedependent L-arginineα-deaminase,γ-hydroxylase in the enduracididine biosynthetic pathway[J].Biochemistry,2015,54(47):7029-7040.
[14]Burroughs A M,Hoppe R W,Goebel N C,et al.Structural and functional characterization of MppR,an enduracididine biosynthetic enzyme from Streptomyces hygroscopicus:functional diversity in the acetoacetate decarboxylase-like superfamily[J].Biochemistry,2013,52(26):4492-4506.
[15]Rudolph J,Hannig F,Theis H,et al.Highly efficient chiralpool synthesis of(2S,4R)-4-hydroxyornithine[J].Org Lett,2001,3(20):3153-3155.
[16]Craig W,Chen J,Richardson D,et al.A highly stereoselective and scalable synthesis of L-allo-enduracididine[J].Org Lett,2015,17(18):4620.
[17]Giltrap A M,Dowman L J,Nagalingam G,et al.Total synthesis of teixobactin[J].Org Lett,2016.18(11):2788-2791.
[18]Dhara S,Gunjal V B,Handore K L,et al.Solution-phase synthesis of the macrocyclic core of teixobactin[J].Eur JOrg Chem,2016,2016(25):4289-4293.
[19]Breukink E,de Kruijff B.Lipid II as a target for antibiotics[J].Nat Rev Drug discov,2006,5(4):321-332.
[20]Xing B,Jiang T,Wu X,et al.Molecular interactions between glycopeptide vancomycin and bacterial cell wall peptide analogues[J].Chemistry,2011,17(50):14170-14177.
[21]Loll P J,Derhovanessian A,Shapovalov M V,et al.Vancomycin forms ligand-mediated supramolecular complexes[J].J Mol Biol,2009,385(1):200-211.
[22]Xie J,Pierce J G,James R C,et al.A redesigned vancomycin engineered for dual D-Ala-D-ala And D-AlaD-Lac binding exhibits potent antimicrobial activity against vancomycin-resistant bacteria[J].J Am Chem Soc,2011,133(35):13946-139469.
[23]Wiedemann I,Breukink E,van Kraaij C,et al.Specific binding of nisin to the peptidoglycan precursor lipid II combines pore formation and inhibition of cell wall biosynthesis for potent antibiotic activity[J].J Biol Chem,2001,276(3):1772-1779.
[24]Hover B M,Kim S H,Katz M,et al.Culture-independent discovery of the malacidins as calcium-dependent antibiotics with activity against multidrug-resistant Gram-positive pathogens[J].Nat Microbiol,(2018)12 February 2018,doi:10.1038/s41564-018-0110-1.
[25]D'Elia M A,Pereira M P,Chung Y S,et al.Lesions in teichoic acid biosynthesis in Staphylococcus aureus lead to a lethal gain of function in the otherwise dispensable pathway[J].J Bacteriol,2006,188(12):4183-4189.
[26]Bierbaum G,Sahl H G.Induction of autolysis of staphylococci by the basic peptide antibiotics Pep 5and nisin and their influence on the activity of autolytic enzymes[J].Arch Microbiol,1985,141(3):249-254.
[27]Liu Y,Liu Y,Chan-Park M B,et al.Binding modes of teixobactin to lipid II:Molecular dynamics study[J].Sci Rep,2017,7(1):17197-17209.
[28]Guo C,Mandalapu D,Ji X,et al.Chemistry and biology of teixobactin.[J].Chemistry,(2017),12,doi:10.1002/chem.201704167.
[29]Jin K,Sam I H,Po K H,et al.Total synthesis of teixobactin[J].Nat Commun,2016,7(11):12394-12399.
[30]Jad Y E,Acosta G A,Naicker T,et al.Synthesis and biological evaluation of a teixobactin analogue[J].Org Lett,2015,17(24):6182-6185.
[31]Parmar A,Iyer A,Vincent C S,et al.Efficient total syntheses and biological activities of two teixobactin analogues[J].Chem Commun,2016,52(36):6060-6063.
[32]Yang H,Chen K H,Nowick J S.Elucidation of the teixobactin pharmacophore[J].ACS Chem Biol,2016,11(7):1823-1826.
[33]Jin K,Po K H L,Wang S,et al.Synthesis and structureactivity relationship of teixobactin analogues via convergent Ser ligation[J].Bioorgan Med Chem,2017,25(18):4990-4995.
[34]Parmar A,Iyer A,Lloyd D G,et al.Syntheses of potent teixobactin analogues against methicillin-resistant Staphylococcus aureus(MRSA)through the replacement of L-allo-enduracididine with its isosteres[J].Chem Commun,2017,53(55):7788-7791.
[35]Parmar A,Lyer A,Prior S H,et al.Teixobactin analogues reveal enduracididine to be non-essential for highly potent antibacterial activity and lipid II binding[J].Chem Sci,2017,8(12):8183-8192.
[36]Parmar A,Prior S H,Iyer A,et al.Defining the molecular structure of teixobactin analogues and understanding their role in antibacterial activities[J].Chem Commun,2017,53(12):2016-2019.
[37]Monaim S A H A,Jad Y E,Acosta G A,et al.Re-evaluation of the N-terminal substitution and the D-residues of teixobactin[J].RSC Adv,2016,6(77):73827-73829.
[38]Monaim S A H A,Jad Y E,Ramchuran E J,et al.Lysine scanning of Arg10-teixobactin:deciphering the role of hydrophobic and hydrophilic residues[J].ACS Omega,2016,1(6):1262-1265.
[39]Chen K H,Le S P,Han X,et al.Alanine scan reveals modifiable residues in teixobactin[J].Chem Commun,2017,53(82):11357-11359.
[40]Yang H,DuBois D R,Ziller J W,et al.X-ray crystallographic structure of a teixobactin analogue reveals key interactions of the teixobactin pharmacophore[J].Chem Commun,2017,53(18):2772-2775.
[41]Abdel Monaim S A H,Ramchuran E J,El-Faham A,et al.Converting teixobactin into a cationic antimicrobial peptide(AMP)[J].J Med Chem,2017,60(17):7476-7482.
[42]Monaim S A H A,Noki S,Ramchuran E J,et al.Investigation of the N-terminus amino function of Arg10-teixobactin[J].Molecules,2017,22(10):1632-1638.
[43]Parmar A,Lakshminarayanan R,Iyer A,et al.Design and syntheses of highly potent teixobactin analogues against Staphylococcus aureus,methicillin-resistant Staphylococcus aureus(MRSA),vancomycin-resistant enterococci(VRE)in vitro and in vivo[J].J Med Chem,2018,61(5):2009-2017.
[44]Mandalapu D,Ji X,Chen J,et al.Thioesterase-mediated synthesis of teixobactin analogues:Mechanism and substrate specificity[J].J Org Chem,2018,1,doi:10.1021/acs.joc.7b02462.
[45]Zhang Y,Buchholz F,Muyrers J P,et al.A new logic for DNA engineering using recombination in Escherichia coli[J].Nat Genet,1998,20(2):123-128.
[46]Fu J,Bian X,Hu S,et al.Full-length RecE enhances linearlinear homologous recombination and facilitates direct cloning for bioprospecting[J].Nat Biotechnol,2012,30(5):440-446.
[47]Wang H,Li Z,Jia R,et al.RecET direct cloning and Redαβrecombineering of biosynthetic gene clusters,large operons or single genes for heterologous expression[J].Nat Prot,2016,11(7):1175-1190.
[48]Wang H,Li Z,Jia R,et al.ExoCET:exonuclease in vitro assembly combined with RecET recombination for highly efficient direct DNA cloning from complex genomes[J].Nucleic Acids Res,2017,46(5):2697-2707.