Regulation of cell wall biosynthesis

抗菌药物新靶位

陈盈盈;张玉彬;顾觉奋

【期刊名称】《中国医药生物技术》

【年(卷),期】2012(007)004

【总页数】4页(P302-305)

【作 者】陈盈盈;张玉彬;顾觉奋

【作者单位】210009,南京,中国药科大学生命科学与技术学院;210009,南京,中国药科大学生命科学与技术学院;210009,南京,中国药科大学生命科学与技术学院

【正文语种】中 文

近年来，由于过度使用抗生素，特别是滥用抗生素，病原菌日益广泛的耐药性已成为药物治疗中越来越常见的问题[1]。为了克服细菌的耐药性，特别是多重耐药性问题，人们需要运用新的思路去发掘新的抗生素，因此，探索新型抗菌机制已成为目前的迫切需要。本文综述了近几年发现的抗菌药物的新靶位，分别从作用于细菌（真菌）细胞壁、细胞膜、RNA 聚合酶、胞内代谢及调控等 4 方面来谈抗菌药物的新作用靶位。

肽聚糖（peptidoglycan）是构成细菌细胞壁的主要成分，革兰阳性和阴性细菌中都含有肽聚糖结构，因此肽聚糖的生物合成途径成为开发广谱抗菌药物的研究热点。

D-丙氨酸是细菌细胞壁中肽聚糖结构的组成成分，主要存在于二肽 D-丙氨酰-D-丙氨酸中，D-丙氨酸直接参与相邻肽聚糖链的交联。在原核生物中，D-丙氨酸的主要合成途径是通过丙氨酸消旋酶（Alr）催化 L-丙氨酸转化而来[2]。

催化肽聚糖合成的胞浆步骤的酶包括烯醇丙酮转移酶MurA、黄素依赖还原酶 MurB 和 ATP 依赖的连接酶MurC、MurD、MurE 和 MurF，通过这些酶的作用，为UDPMurNAc 乙酰基侧链添加 L-丙氨酸、D-谷氨酸、内消旋二氨基庚二酸（M-DAP）或 L-赖氨酸、D-丙氨酸-D-丙氨酸二肽，生成 UDPMurNAc-五肽，之后移位酶 MraY 和糖基转移酶 MurG 催化 UDPMurNAc-五肽转化为脂质中间体 I 和 II。

某些革兰阳性菌酶，如金黄色葡萄球菌 FemABX 酶以甘氨酰-tRNA 为底物，增加

Galacturonosyltransferase(GAUT)1andGAUT7

arethecoreofaplantcellwallpectinbiosynthetic

homogalacturonan:galacturonosyltransferasecomplex

MelaniA.Atmodjoa,b,YumikoSakuragic,d,1,XiangZhua,1,AmyJ.Burrella,SushreeS.Mohantya,e,JamesA.AtwoodIIIa,2,

RonOrlandoa,HenrikV.Schellerc,f,andDebraMohnena,b,e,3

aComplexCarbohydrateResearchCenter,bDepartmentofBiochemistryandMolecularBiology,andeBioEnergyScienceCenter,UniversityofGeorgia,Athens,

GA30602;cDepartmentofPlantBiologyandBiotechnologyanddVillumKannRasmussenResearchCentrePro-ActivePlants,UniversityofCopenhagen,

DK-1871FrederiksbergC,Copenhagen,Denmark;andfJointBioEnergyInstitute,LawrenceBerkeleyNationalLaboratory,Emeryville,CA94608

Edited*byDeborahP.Delmer,TheRockefellerFoundation,NewYork,NY,andapprovedOctober19,2011(receivedforreviewAugust16,2011)

Plantcellwallpecticpolysaccharidesarearguablythemostcomplex

GeneFunctionFold changeFMP48Putative protein of unknown function49,51PHM8Protein of unknown function; expression is induced by low phosphate levels36,54HSP30Hydrophobic stress-responsive protein of the plasma membrane that negatively regulates Pma1p H+-ATPase activity31,60BTN2v-SNARE binding protein involved in protein retrieval from the late endosome to Golgi compartment30,95SSE2Heat shock protein of the HSP70 family14,66SSA4Heat shock protein of the HSP70 family12,95TPO2Plasma membrane spermine transporter of the Major Facilitator Superfamily12,22HSP42Small heat shock protein (sHSP) with chaperone activity11,51YPR157wPutative protein of unknown function11,09YAL061wPutative medium-chain alcohol dehydrogenase10,81TOS3Protein kinase involved in phosphorylation and activation of Snf1p10,65SPI1GPI-anchored cell wall protein involved in weak acid resistance10,27TOS8Homeodomain-containing transcription factor that regulates expression of genes involved in G1/S phase events10,19ROG3Unknown function; binds to ubiquitin ligase Rsp5p9,39YER130cUnknown function9,15YGR250cUnknown function9,05YBR099cUnknown function8,79YLR297wUnknown function8,69YAR029wUnknown function8,60YJL144wCytoplasmic hydrophilin of unknown function possibly involved in the dessication response8,39APJ1Putative chaperone of the HSP40 (DNAJ) family8,16HSP78Oligomeric mitochondrial matrix chaperone that prevents the aggregation of misfolded matrix proteins7,66HSP104Heat shock protein that involved in protein refolding7,09YRO2Putative protein of unknown function6,81YOL014wPutative protein of unknown function6,80YDR222wPutative protein of unknown function6,80SKS1Serine/threonine protein kinase involved in the adaptation to low concentrations of glucose6,59UGA2Succinate semialdehyde dehydrogenase6,52BAG7Rho GTPase activating protein (RhoGAP) that stimulates activity of Rho1p6,42PDC5Minor isoform of pyruvate decarboxylase6,24YNR034w-aPutative protein of unknown function6,03PHD1Transcriptional activator involved in pseudohyphal growth5,92Supp. Table 1 - Up-regulated genes after 45 minutes of exposure of S. cerevisiae BY4741 to 20 mM propionic acid obtained in the microarrays analysis carried out. Genes whose transcript levels were activated by more than 2-fold, compared with mRNA values registered in control cells, were selected and are presented. Gene function is also shown based on the information available at SGD ().ICS2Putative protein of unknown function5,92MGA1Putative transcription factor similar to Hsf1p5,88YKL044wPutative protein of unknown function5,71YPC1Alkaline ceramidase involved in ceramide catabolism5,69HSP82Hsp90 chaperone5,59YPL014wPutative protein of unknown function5,52PIC2Mitochondrial phosphate carrier that imports inorganic phosphate into mitochondria5,43MSN4Transcriptional activator activated in stress conditions involved in general stress response5,26YPR158wPutative protein of unknown function5,14ISF1Serine-rich, hydrophilic uncharacterized mithocondrial protein4,64HSP26Small heat shock protein (sHSP) with chaperone activity4,46STP4Similar to transcription factors Stp1p and Stp2p4,46YCR062WPutative protein of unknown function4,31FES1Hsp70 (Ssa1p) nucleotide exchange factor4,24YMR320wPutative protein of unknown function4,16YBR085c-aPutative protein of unknown function4,10MDJ1Protein involved in folding of mitochondrially synthesized proteins in the mitochondrial matrix4,06ADI1Acireductone dioxygenease involved in the methionine salvage pathway3,98AST1Membrane protein involved in targeting to the plasma membrane of Pma1p3,96JIP4Putative protein of unknown function3,72CMK2Calmodulin-dependent protein kinase that may play a role in stress response3,68SOK2Nuclear protein that plays a regulatory role in the cyclic AMP (cAMP)-dependent signal transduction pathway; involved in pseudohyphal growth3,68RTS3Putative component of the protein phosphatase type 2A complex3,62JID1Probable Hsp40p co-chaperone that appears to be involved in ER-associated degradation of misfolded proteins3,56OPI10Protein with a possible role in phospholipid biosynthesis3,54PDR12Plasma membrane ATP-binding cassette (ABC) transporter required for weak organic acid resistance3,50RMA1Putative dihydrofolate synthetase3,47VHS1Cytoplasmic serine/threonine protein kinase possibly involved in G1/S phase progression3,46ICY1Protein of unknown function3,45YCR061wProtein of unknown function3,44ROX1Heme-dependent repressor of hypoxic genes3,42SIS1Co-chaperone of the HSP40 family3,41YGP1Uncharacterized cell wall-related glycoprotein3,40YIR035cPutative cytoplasmic protein of unknown function3,30EDC2RNA-binding protein involved in mRNA decapping3,24MSC1Protein of unknown function3,19YMR181cProtein of unknown function3,18YGR251wPutative protein of unknown function3,15YJR096wPutative xylose and arabinose reductase3,12

青霉素类抗生素

AMOXICILLIN

CAS NUMBER : 26787-78-0

EINECS NUMBER : 248-003-8

CHEMICAL NAME(S):

(2S,5R,6R)-6-[(R)-(-)-2-amino-2-(p-hydroxyphenyl) acetamido]-3,3-

dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0] heptane-2-carboxylic acid

BRAND NAME(S): Amoxil; Polymox; Trimox;

CLASSIFICATIONIFICATION: Antibiotic > beta-Lactam Antibiotics > Penicillin

SPECIFICATION : USP, BP, JP, EP C16H19N3O5S (365.40)

AMPICILLIN

CAS NUMBER : 69-53-4 (Anhydrous), 7177-48-2 (Trihydrate)

EINECS NUMBER : 200-709-7

CHEMICAL NAME(S):

(2S,5R,6R)-6-[(R)-2-Amino-2-phenylacetamido]-3,3-dimethyl- 7-oxo-

4-thia-1-azabicyclo[3.2.0]heptane-2- carboxylic acid;

D(-)-alpha-Aminobenzylpenicillin;

BRAND NAME(S):

CLASSIFICATION: Antibiotic > beta-Lactam Antibiotics > Penicillin

SPECIFICATION : USP, BP, JP, EP C16H19N3O4S (349.40)

AMPICILLIN SODIUM