微生物来源卤化天然产物研究进展*

王荫荫，邵美云，岳昌武

(遵义医学院医学与生物学研究中心 贵州省微生物资源及药物开发特色重点实验室，贵州 遵义　563099)



综述

微生物来源卤化天然产物研究进展*

王荫荫，邵美云，岳昌武

(遵义医学院医学与生物学研究中心 贵州省微生物资源及药物开发特色重点实验室，贵州 遵义563099)

卤化天然产物特别是微生物来源卤化天然产物在生理和生物化学上具有重要作用，是抗生素类药物的重要来源，在控制病原微生物特别是耐药菌感染方面发挥着重要作用。本文综述了近年来发现的放线菌、真菌及其它微生物来源的卤化天然产物及其应用前景。

卤化天然产物；抗生素；真菌；放线菌

放线菌的大部分次生代谢产物通过聚酮合酶(polyketicle synthase,PKS)和非核糖体肽合成酶(no ribosomal peptide synthase,NRPS)途径合成[1]，称后修饰酶的卤化酶对其生物活性影响较大，卤化取代的位置、数目及取代基的种类(见图1)使抗生素的活性有所改变[2,16-17]。苯基恶唑环卤原子单取代比相应双取代对抗肿瘤的效果强[3]；新生霉素氯化修饰后对人体热休克蛋白90抑制活性增加[4]；2010年加州大学William Fenical研究组发现的fijiolides A、B在九元稀二炔母核上多一个氯原子取代从而对HCT-116人结肠癌细胞和耐甲氧西林金黄色葡萄球菌无显著抑制活性[5]；含氯海洋来源药物salinosporamide A具有抗肿瘤作用[6]；含溴药物奥溴克新(oxabrexine)具有祛痰镇咳作用、含碘药物卡奇霉素(calicheamicin)同样显示出抗肿瘤活性[7]。在卤化代谢物中，陆生微生物主要产

氯化代谢物，溴化代谢物则主要由海洋微生物产生，尽管地壳组成中含量最多的卤素是氟，但在生物体中碘化代谢物和氟化代谢物都比较少[8-10]。

图1　放线菌中卤化天然产物

微生物来源卤化天然产物具有良好的生物活性、较低的毒性等特点，在成药潜力方面具有化学合成药不可比拟的优点潜力，目前临床应用的绝大部分卤化抗生素都是来自微生物或其骨架经人工修饰的半合成产物[11-12]，微生物来源的具有较高医学应用价值的卤化代谢物蝴蝶霉素和刺孢霉素均属抗癌药物，FDA在2014年批准上市的4个新型抗生素中，有三个是卤化产物Dalvance (dalbavancin，达巴万星)、新恶唑烷酮类抗菌素Sivextro (tedizolid phosphate，磷酸泰地唑胺)、Orbactiv (Oritavanci，奥利万星)[13-15]，因此，越来越多的研究者将目光转向了微生物来源卤化天然产物。本课题组对76种微生物来源的卤化产物的生源进行了统计，结果表明卤化天然产物来源以真菌为主(55.2%)，其次是放线菌(35.5%)，蓝细菌和其它类微生物占了不到一成(9.3%)，提示我们真菌和放线菌依然是微生物卤化天然产物重要来源。本文微生物来源卤化物的结构、生物活性及其研究现状进行综述，以期为新型微生物来源卤化产物挖掘提供借鉴。

1　放线菌来源天然卤化产物

土壤来源的放线菌是微生物来源卤化天然产物的主要来源，从稀有放线菌发酵产物中分离出含氯吩嗪类化合物chlorophenazine (1)早期在临床用于治疗麻风杆菌感染，近几年发现有很强的体内外抗结核活性，对多耐药结核分枝杆菌有杀菌作用[16]。链霉菌Streptomyces carzinostaticus的菌丝体中分离得到具有较好的抗白血病活性的聚酮类含氯化合物neocarzillin A (2)[17]。海洋放线菌CNH-099中分离到有细胞毒作用的倍半萜醌类抗生素marinonc 衍生物 isomarinone ，对结肠癌细胞HCr-116的IC50值是8.0 μg/m[18]。Actinomadurasp.HQ24的代谢物中发现一种新的具有细胞保护作用的含噻唑啉环新骨架卤化物trichloropyrrole[19-20]。 Tsukamoto等从链霉菌A19412中得到抗肿瘤氯化物BE-19412A，及其甲基化修饰产物BE-19412B，这两个含氯化合物对人体和小鼠肿瘤细胞均具有很强的抗肿瘤活性[21]。Li等从链霉菌Streptomycessp.M045中发现对人体不同肿瘤细胞具有抑制作用的新型聚酮类化合物chinikomycins A[22]。Liu T等从Myrothecium sp.GS-17中分离得到两个卤素取代含香豌豆醇类化合物对癌细胞具有较强的细胞毒性[23]。本课题组从土壤链霉菌Streptomyces SP.FJS31-2中发现卤化二型聚酮类zunyimycinA(见图2)。

图2　zunyimycin A

随着研究的进展，从陆地生态环境发现新抗生素可能性越来越小，研究者将目光转向海洋、温泉及沙漠等特殊生境[24]，Asolkar等对海洋链霉菌CNQ-525来源的三个含氯醌类化合物Daryamides A-C活性分析，该类化合物对人结肠癌细胞HCT-116显示出微弱的细胞毒活性，同时对白色念珠菌有一定的抑菌作用[25]。Maloney等人从分自海洋放线菌Saccharomonosporasp.发现了一种全新的含卤生物碱lodopyridone，对人结肠癌细胞HCT-116的IC50值为3.6 μmol/L[26]。Kim从盐场衍生放线菌次级代谢产物中分离得到一系列manumycin类化合物Salternamides A-D，其中卤化物Salternamide A 对人结肠癌细胞HCT-116和胃癌细胞SNU638有抑制作用[27]。Kauffman等从海洋放线菌Salinisporapacifica中鉴定2个结构新颖的环戊二烯并茚苷化合物cyanosporasides A和B，其对人结肠癌细胞HCT-116具有较弱的细胞毒性，其IC50值为30.0μg/mL[28]。Cheol等从海洋放线菌中鉴定streptochlorin，该化合物对人白血病细胞U937具有促凋亡作用，对白血病细胞K-562的IC50值为1.05μg/mL[29]。McArthur等从海洋放线菌NPS12745中发现了一系列氯化双吲哚类化合物lynamicins A-E，该系列化合物对革兰氏阳性菌和革兰氏阴性菌均有较好的抗菌活性，对耐万古霉素肠球菌和耐甲氧西林金黄色葡萄球菌具有一定的抑制作用[30]。Chambers等从深海放线菌CNQ-418中分离到一系列具有吡咯母核的含卤新化合物marinopyrroles A和B，其对耐甲氧西林金黄色葡萄球菌具有较强的抗菌活性[31]。

2　真菌来源天然卤化产物

和放线菌一样，真菌来源的卤化天然产物也丰富了含卤素化合物的资源(见图2)，特殊生境的真菌备受研究者关注。土壤真菌中发现和磷霉素类似物的新型抗生素fosfonochlorin对多种革兰氏阴性菌抑菌作用强于磷霉素及氯霉素，并可抑制细菌原生质体的形成[32]。Y Mou对土壤真菌Coniothyriumsp.中的卤化物palmarumycin结构进行修饰得到的衍生物对细菌和真菌具有抑菌效果，对肿瘤细胞也有一定的作用[33]。Jansen等从土壤真菌顶多毛孢属LF550中发现了两种新卤化物isochromophilones X (3)和XI，这两种化合物可以抑制酯酰辅酶A-胆固醇酰基转移酶(ACAT)和二酰甘油酰基转移酶(DGAT)[34]。Itabashi等从土壤真菌Emericellafalconensis中分离到含氯萜类新化合物，该化合物对ACAT和DGAT具有抑制活性[35]。Akone等从植物内生真菌Pestalotiopsis中发现了血管紧张素Ⅱ受体拮抗剂cytosporin B (4)类似物，对金黄色葡萄球菌和大肠埃希菌有抑菌作用，其ID50值为64 μg/mL[36]。Ying对海洋真菌Fusarium.sp.s来源的二倍半萜新化合物neomangicols A结构进行研究，卤化后的衍生物对人结肠癌细胞HCT-116有活性[37]。Amagata等从海绵附生真菌TrichodermaharzianumOUPS-N115中发现一系列卤化物，对肿瘤细胞P388表现出较强的抑制作用，其ED值分别是1.41和1.21 μg/mL[38]。 Haque等从孟加拉国红树林孙德尔本斯链霉菌Streptomycessp.ANAM-5和ANAM-10来源中分离到氯化苯甲酮抗生素pestalone，该化合物对耐甲氧西林金黄色葡萄球菌和耐万古霉素肠球菌均有抗菌活性[39]。Amagata等从海绵附生真菌Gymnascelladankaliensis菌丝体甲醇提取物中分离得到1个含有独特的双环壬烷结构的卤化物gymnamide G，当把培养基中的葡萄糖换成可溶性淀粉后，发现该菌产生了四个新卤化物dankaliensis A 和B、gymnamide Q和R[40]，这些化合物对肿瘤细胞P388具有抑制作用，且化合物gymnamide Q对人乳腺癌细胞BSY-1和胃癌细胞MKN7均有抑制作用，当培养基中添加溴元素，该真菌能产生一系列溴化物gymnastatins I-K ,该类化合物对P388等多种人癌细胞的生长均表现出明显的抑制作用[41]。

Chen等从海洋真菌Penicilliumterrestre中发现了一类2，5-二羟基苯甲醇氯代衍生物，这类化合物对细胞BEL-7402、MOLT-4、HL-60和A-549均表现出较弱的细胞毒性，其IC50值范围为5.0～65.0 μmol/L。此外，所有新化合物均表现出较好的清除自由基功能，其IC50值范围为2.6～8.5 μmol/L[42]。Iritani M等从Periconiabyssoides中分离得到三个新化合pericosines A、D和E，pericosines A和D对肿瘤细胞株的生长具有显著抑制作用，且pericosine A 显示很好的体内肿瘤抑制作用及抑制拓扑异构酶II和蛋白激酶EGFR[43]。Yamada等从海鱼Mugilcephalus内生真菌Chaetomiumglobosum中分离到一系列对HL-60和P388细胞的生长具有抑制作用的化合物chaetomugilins A、C和F，A化合物对L1210、P388、KB和HL-60细胞均表现出较好的抑制作用[44-45]。化合物F选择性对人癌细胞具有的抑制作用[46]。Zhang等从海绵Halichondriapanacea附生真菌Exophialasp.中获得对金黄色葡萄球菌、耐甲氧西林金葡菌和多耐药金黄色葡萄球菌具有温和的抗菌活性的chlorohydroaspyrones A和B[47]。Muroga等从真菌Chaetomiumglobosum的代谢产物中，分离鉴定了化合物chaetomugilins A的同分异构体4-epi-chaetomugilin 和11-epi-chaetomugilin，其活性研究表明，化合物11-epichaetgilin对HL-60和P388细胞具有中等的细胞毒活性，其IC50值分别为66.7和88.9 μg/mL，而化合物4-epichaetomugilin活性则较弱[48]。Nenkep等在褐藻真菌Fusariumtricinctum中发现两个新的抗菌溴化物bromomethyl-Chlamydosporols-A和B，对耐甲氧西林金黄色葡萄球菌、金黄色葡萄球菌的IC50值均为31.5 μg/mL，对多耐药金黄色葡萄球菌的IC50值为62.5 μg/mL[49]。Li等从海绵附生真菌98F134的发酵产物中分离得到一个卤化产物(-)-Sclerotiorin，可通过1-甲基腺嘌呤来抑制海星卵母细胞的成熟，其IC50值为0.5 μmol/L，同时该化合物对酵母菌、烟曲霉菌、稻瘟病菌、黄萎菌和黄色镰刀菌等真菌均表现出广谱的抑制作用，其IC50值均低于20.0 μg/mL[50]。Yun等从海洋真菌Chrysosporiumsynchronum中得到2-O-(α-D-mannopyranosyl-5-hydroxy-3-Chloroben-zylalcoho，该化合物具有很强的清除DPPH自由基抗氧化活性，其IC50值为4.7 μmol/L[51]。Wang等从海洋真菌曲丽穗霉SpicariaelegansKLA-03中分离到含氯新化合物trichodermamide B，该化合物对铜绿假单胞菌Pseudomonasaeruginosa和大肠杆菌Escherichiacoli均有抑制作用，其IC50值分别为0.038和0.767 mmol/L[52]。

图3　真菌来源的卤化天然产物

3　其它微生物来源的天然卤代产物

除了放线菌和真菌之外，人们还从一些稀有甚至是致病菌种发现了一系列活性卤化天然产物，如Liu从Pseudomonassp.No.2663中的FR901464发现一种新的抗肿瘤化合物spliceostatin B 进行分离纯化得到单体化合物，该化合物能明显提高病毒DNA SV40启动子转录活性，且对小鼠和人肿瘤细胞具有较强的抑制作用[53]。Funakoshi等从Amycolatopsissp.中发现新化合物epoxyquinomicins A，该化合物对革兰氏阳性菌具有较好的抗菌活性[54]。Shaala等从蓝细菌Lyngbyamajuscula中分离到Malyngamides类新化合物Malyngamides 4，该化合物具有与已知化合物Malyngamides相似的虾毒性[55]。Orfali等从蓝细菌Lyngbyamajuscula中发现Malyngamides R结构类似物isomalyngamides A和B[56]。 Hendtik 等从蓝细菌Lyngbyasp.中发现大环内酯苷类化合物lyngbyaloside B，该化合物对LoVo细胞有抑制作用，其IC50值约为15 μmol/L[57]。Thomas等从蓝细菌Phormidiumsp.中分离到大环内酯类卤代物phormidolide，该化合物对盐水虾具有高毒性，其IC50值为1.5 μmol/L[58]。

4　展望

鉴于微生物来源卤化天然产物的巨大成药潜力和人类面临的耐药菌的重大威胁，从微生物卤化天然产物中发现新抗生素是人们应对“超级菌”的一个有效策略。然而，常规手段的产物分离不可避免会遇到“重复发现”的难题。如何破解这个难题，是抗生素开发研究人员面临的重要考验。以基因组学、转录组、代谢组学等为代表组学技术和现代分析测试技术进步为人们提供了有力的武器。研究者可通过次级代谢合成或修饰基因筛选(尤其是卤化酶基因筛选)从大量的分离菌株中筛选出潜力菌株，结合次级代谢基因表达水平分析优化出卤化产物高效合成的发酵条件，在此基础结合高分辨质谱等手段对次级代谢产物谱进行分析，最终确定卤化天然产物生物合成条件，发酵纯化制备并获得相应的产物。本课题组利用这些技术，从1000余株贵州不同生境来源的分离菌株中确定梵净山土壤来源的链霉菌Streptomycessp.FJS31-2为出发菌株，通过优化表达谱分析示踪卤化产物合成，最终获得新型抗耐甲氧西林金黄色葡萄球菌的卤化二型聚酮类抗生素zunyimycin A并鉴定了其生物合成基因簇[39]。这表明，只要手段得当，通过不同培养条件及外界刺激等，研究者发现更多结构多样及复杂的新型活性卤化产物，为新药开发提供先导化合物还是切实可行。

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[收稿2016-06-05;修回2016-07-08]

(编辑：王福军)

Research development of halogenated natural products derived microorganisms

WangYinyin,ShaoMeiyun,YueChangwu

(Guizhou Key Laboratory of Microbial Resources & Drug Development,Zunyi Medical University， Zunyi Guizhou 563099，China)

Microbial derived halogenated natural products tend possess very important biological and physiological activities,especially against the drug-resistant bacteria infection or antitumor,therefore,is an important source of antibiotic.In this paper,halogenated natural products isolated from actinomycetes,fungi as well as the other microorganisms and their application potential in recent years were reviewed.

halogenated natural products； antibiotics； fungi；actinomycetes.

国家自然科学基金资助项目(NO：31160004)。

岳昌武，男，博士，副研究员，硕士生导师，研究方向：微生物天然产物生物合成，E-mail:changwuyue@126.com。

Q93

A

1000-2715(2016)04-0435-06