微生物來源鹵化天然產(chǎn)物研究進(jìn)展*

王蔭蔭，邵美云，岳昌武

(遵義醫(yī)學(xué)院醫(yī)學(xué)與生物學(xué)研究中心 貴州省微生物資源及藥物開發(fā)特色重點實驗室，貴州 遵義　563099)

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綜述

微生物來源鹵化天然產(chǎn)物研究進(jìn)展*

王蔭蔭，邵美云，岳昌武

(遵義醫(yī)學(xué)院醫(yī)學(xué)與生物學(xué)研究中心 貴州省微生物資源及藥物開發(fā)特色重點實驗室，貴州 遵義563099)

鹵化天然產(chǎn)物特別是微生物來源鹵化天然產(chǎn)物在生理和生物化學(xué)上具有重要作用，是抗生素類藥物的重要來源，在控制病原微生物特別是耐藥菌感染方面發(fā)揮著重要作用。本文綜述了近年來發(fā)現(xiàn)的放線菌、真菌及其它微生物來源的鹵化天然產(chǎn)物及其應(yīng)用前景。

鹵化天然產(chǎn)物；抗生素；真菌；放線菌

放線菌的大部分次生代謝產(chǎn)物通過聚酮合酶(polyketicle synthase,PKS)和非核糖體肽合成酶(no ribosomal peptide synthase,NRPS)途徑合成[1]，稱后修飾酶的鹵化酶對其生物活性影響較大，鹵化取代的位置、數(shù)目及取代基的種類(見圖1)使抗生素的活性有所改變[2,16-17]。苯基惡唑環(huán)鹵原子單取代比相應(yīng)雙取代對抗腫瘤的效果強(qiáng)[3]；新生霉素氯化修飾后對人體熱休克蛋白90抑制活性增加[4]；2010年加州大學(xué)William Fenical研究組發(fā)現(xiàn)的fijiolides A、B在九元稀二炔母核上多一個氯原子取代從而對HCT-116人結(jié)腸癌細(xì)胞和耐甲氧西林金黃色葡萄球菌無顯著抑制活性[5]；含氯海洋來源藥物salinosporamide A具有抗腫瘤作用[6]；含溴藥物奧溴克新(oxabrexine)具有祛痰鎮(zhèn)咳作用、含碘藥物卡奇霉素(calicheamicin)同樣顯示出抗腫瘤活性[7]。在鹵化代謝物中，陸生微生物主要產(chǎn)

氯化代謝物，溴化代謝物則主要由海洋微生物產(chǎn)生，盡管地殼組成中含量最多的鹵素是氟，但在生物體中碘化代謝物和氟化代謝物都比較少[8-10]。

圖1　放線菌中鹵化天然產(chǎn)物

微生物來源鹵化天然產(chǎn)物具有良好的生物活性、較低的毒性等特點，在成藥潛力方面具有化學(xué)合成藥不可比擬的優(yōu)點潛力，目前臨床應(yīng)用的絕大部分鹵化抗生素都是來自微生物或其骨架經(jīng)人工修飾的半合成產(chǎn)物[11-12]，微生物來源的具有較高醫(yī)學(xué)應(yīng)用價值的鹵化代謝物蝴蝶霉素和刺孢霉素均屬抗癌藥物，F(xiàn)DA在2014年批準(zhǔn)上市的4個新型抗生素中，有三個是鹵化產(chǎn)物Dalvance (dalbavancin，達(dá)巴萬星)、新惡唑烷酮類抗菌素Sivextro (tedizolid phosphate，磷酸泰地唑胺)、Orbactiv (Oritavanci，奧利萬星)[13-15]，因此，越來越多的研究者將目光轉(zhuǎn)向了微生物來源鹵化天然產(chǎn)物。本課題組對76種微生物來源的鹵化產(chǎn)物的生源進(jìn)行了統(tǒng)計，結(jié)果表明鹵化天然產(chǎn)物來源以真菌為主(55.2%)，其次是放線菌(35.5%)，藍(lán)細(xì)菌和其它類微生物占了不到一成(9.3%)，提示我們真菌和放線菌依然是微生物鹵化天然產(chǎn)物重要來源。本文微生物來源鹵化物的結(jié)構(gòu)、生物活性及其研究現(xiàn)狀進(jìn)行綜述，以期為新型微生物來源鹵化產(chǎn)物挖掘提供借鑒。

1　放線菌來源天然鹵化產(chǎn)物

土壤來源的放線菌是微生物來源鹵化天然產(chǎn)物的主要來源，從稀有放線菌發(fā)酵產(chǎn)物中分離出含氯吩嗪類化合物chlorophenazine (1)早期在臨床用于治療麻風(fēng)桿菌感染，近幾年發(fā)現(xiàn)有很強(qiáng)的體內(nèi)外抗結(jié)核活性，對多耐藥結(jié)核分枝桿菌有殺菌作用[16]。鏈霉菌Streptomyces carzinostaticus的菌絲體中分離得到具有較好的抗白血病活性的聚酮類含氯化合物neocarzillin A (2)[17]。海洋放線菌CNH-099中分離到有細(xì)胞毒作用的倍半萜醌類抗生素marinonc 衍生物 isomarinone ，對結(jié)腸癌細(xì)胞HCr-116的IC50值是8.0 μg/m[18]。Actinomadurasp.HQ24的代謝物中發(fā)現(xiàn)一種新的具有細(xì)胞保護(hù)作用的含噻唑啉環(huán)新骨架鹵化物trichloropyrrole[19-20]。 Tsukamoto等從鏈霉菌A19412中得到抗腫瘤氯化物BE-19412A，及其甲基化修飾產(chǎn)物BE-19412B，這兩個含氯化合物對人體和小鼠腫瘤細(xì)胞均具有很強(qiáng)的抗腫瘤活性[21]。Li等從鏈霉菌Streptomycessp.M045中發(fā)現(xiàn)對人體不同腫瘤細(xì)胞具有抑制作用的新型聚酮類化合物chinikomycins A[22]。Liu T等從Myrothecium sp.GS-17中分離得到兩個鹵素取代含香豌豆醇類化合物對癌細(xì)胞具有較強(qiáng)的細(xì)胞毒性[23]。本課題組從土壤鏈霉菌Streptomyces SP.FJS31-2中發(fā)現(xiàn)鹵化二型聚酮類zunyimycinA(見圖2)。

圖2　zunyimycin A

隨著研究的進(jìn)展，從陸地生態(tài)環(huán)境發(fā)現(xiàn)新抗生素可能性越來越小，研究者將目光轉(zhuǎn)向海洋、溫泉及沙漠等特殊生境[24]，Asolkar等對海洋鏈霉菌CNQ-525來源的三個含氯醌類化合物Daryamides A-C活性分析，該類化合物對人結(jié)腸癌細(xì)胞HCT-116顯示出微弱的細(xì)胞毒活性，同時對白色念珠菌有一定的抑菌作用[25]。Maloney等人從分自海洋放線菌Saccharomonosporasp.發(fā)現(xiàn)了一種全新的含鹵生物堿lodopyridone，對人結(jié)腸癌細(xì)胞HCT-116的IC50值為3.6 μmol/L[26]。Kim從鹽場衍生放線菌次級代謝產(chǎn)物中分離得到一系列manumycin類化合物Salternamides A-D，其中鹵化物Salternamide A 對人結(jié)腸癌細(xì)胞HCT-116和胃癌細(xì)胞SNU638有抑制作用[27]。Kauffman等從海洋放線菌Salinisporapacifica中鑒定2個結(jié)構(gòu)新穎的環(huán)戊二烯并茚苷化合物cyanosporasides A和B，其對人結(jié)腸癌細(xì)胞HCT-116具有較弱的細(xì)胞毒性，其IC50值為30.0μg/mL[28]。Cheol等從海洋放線菌中鑒定streptochlorin，該化合物對人白血病細(xì)胞U937具有促凋亡作用，對白血病細(xì)胞K-562的IC50值為1.05μg/mL[29]。McArthur等從海洋放線菌NPS12745中發(fā)現(xiàn)了一系列氯化雙吲哚類化合物lynamicins A-E，該系列化合物對革蘭氏陽性菌和革蘭氏陰性菌均有較好的抗菌活性，對耐萬古霉素腸球菌和耐甲氧西林金黃色葡萄球菌具有一定的抑制作用[30]。Chambers等從深海放線菌CNQ-418中分離到一系列具有吡咯母核的含鹵新化合物marinopyrroles A和B，其對耐甲氧西林金黃色葡萄球菌具有較強(qiáng)的抗菌活性[31]。

2　真菌來源天然鹵化產(chǎn)物

和放線菌一樣，真菌來源的鹵化天然產(chǎn)物也豐富了含鹵素化合物的資源(見圖2)，特殊生境的真菌備受研究者關(guān)注。土壤真菌中發(fā)現(xiàn)和磷霉素類似物的新型抗生素fosfonochlorin對多種革蘭氏陰性菌抑菌作用強(qiáng)于磷霉素及氯霉素，并可抑制細(xì)菌原生質(zhì)體的形成[32]。Y Mou對土壤真菌Coniothyriumsp.中的鹵化物palmarumycin結(jié)構(gòu)進(jìn)行修飾得到的衍生物對細(xì)菌和真菌具有抑菌效果，對腫瘤細(xì)胞也有一定的作用[33]。Jansen等從土壤真菌頂多毛孢屬LF550中發(fā)現(xiàn)了兩種新鹵化物isochromophilones X (3)和XI，這兩種化合物可以抑制酯酰輔酶A-膽固醇酰基轉(zhuǎn)移酶(ACAT)和二酰甘油?；D(zhuǎn)移酶(DGAT)[34]。Itabashi等從土壤真菌Emericellafalconensis中分離到含氯萜類新化合物，該化合物對ACAT和DGAT具有抑制活性[35]。Akone等從植物內(nèi)生真菌Pestalotiopsis中發(fā)現(xiàn)了血管緊張素Ⅱ受體拮抗劑cytosporin B (4)類似物，對金黃色葡萄球菌和大腸埃希菌有抑菌作用，其ID50值為64 μg/mL[36]。Ying對海洋真菌Fusarium.sp.s來源的二倍半萜新化合物neomangicols A結(jié)構(gòu)進(jìn)行研究，鹵化后的衍生物對人結(jié)腸癌細(xì)胞HCT-116有活性[37]。Amagata等從海綿附生真菌TrichodermaharzianumOUPS-N115中發(fā)現(xiàn)一系列鹵化物，對腫瘤細(xì)胞P388表現(xiàn)出較強(qiáng)的抑制作用，其ED值分別是1.41和1.21 μg/mL[38]。 Haque等從孟加拉國紅樹林孫德爾本斯鏈霉菌Streptomycessp.ANAM-5和ANAM-10來源中分離到氯化苯甲酮抗生素pestalone，該化合物對耐甲氧西林金黃色葡萄球菌和耐萬古霉素腸球菌均有抗菌活性[39]。Amagata等從海綿附生真菌Gymnascelladankaliensis菌絲體甲醇提取物中分離得到1個含有獨特的雙環(huán)壬烷結(jié)構(gòu)的鹵化物gymnamide G，當(dāng)把培養(yǎng)基中的葡萄糖換成可溶性淀粉后，發(fā)現(xiàn)該菌產(chǎn)生了四個新鹵化物dankaliensis A 和B、gymnamide Q和R[40]，這些化合物對腫瘤細(xì)胞P388具有抑制作用，且化合物gymnamide Q對人乳腺癌細(xì)胞BSY-1和胃癌細(xì)胞MKN7均有抑制作用，當(dāng)培養(yǎng)基中添加溴元素，該真菌能產(chǎn)生一系列溴化物gymnastatins I-K ,該類化合物對P388等多種人癌細(xì)胞的生長均表現(xiàn)出明顯的抑制作用[41]。

Chen等從海洋真菌Penicilliumterrestre中發(fā)現(xiàn)了一類2，5-二羥基苯甲醇氯代衍生物，這類化合物對細(xì)胞BEL-7402、MOLT-4、HL-60和A-549均表現(xiàn)出較弱的細(xì)胞毒性，其IC50值范圍為5.0～65.0 μmol/L。此外，所有新化合物均表現(xiàn)出較好的清除自由基功能，其IC50值范圍為2.6～8.5 μmol/L[42]。Iritani M等從Periconiabyssoides中分離得到三個新化合pericosines A、D和E，pericosines A和D對腫瘤細(xì)胞株的生長具有顯著抑制作用，且pericosine A 顯示很好的體內(nèi)腫瘤抑制作用及抑制拓?fù)洚悩?gòu)酶II和蛋白激酶EGFR[43]。Yamada等從海魚Mugilcephalus內(nèi)生真菌Chaetomiumglobosum中分離到一系列對HL-60和P388細(xì)胞的生長具有抑制作用的化合物chaetomugilins A、C和F，A化合物對L1210、P388、KB和HL-60細(xì)胞均表現(xiàn)出較好的抑制作用[44-45]。化合物F選擇性對人癌細(xì)胞具有的抑制作用[46]。Zhang等從海綿Halichondriapanacea附生真菌Exophialasp.中獲得對金黃色葡萄球菌、耐甲氧西林金葡菌和多耐藥金黃色葡萄球菌具有溫和的抗菌活性的chlorohydroaspyrones A和B[47]。Muroga等從真菌Chaetomiumglobosum的代謝產(chǎn)物中，分離鑒定了化合物chaetomugilins A的同分異構(gòu)體4-epi-chaetomugilin 和11-epi-chaetomugilin，其活性研究表明，化合物11-epichaetgilin對HL-60和P388細(xì)胞具有中等的細(xì)胞毒活性，其IC50值分別為66.7和88.9 μg/mL，而化合物4-epichaetomugilin活性則較弱[48]。Nenkep等在褐藻真菌Fusariumtricinctum中發(fā)現(xiàn)兩個新的抗菌溴化物bromomethyl-Chlamydosporols-A和B，對耐甲氧西林金黃色葡萄球菌、金黃色葡萄球菌的IC50值均為31.5 μg/mL，對多耐藥金黃色葡萄球菌的IC50值為62.5 μg/mL[49]。Li等從海綿附生真菌98F134的發(fā)酵產(chǎn)物中分離得到一個鹵化產(chǎn)物(-)-Sclerotiorin，可通過1-甲基腺嘌呤來抑制海星卵母細(xì)胞的成熟，其IC50值為0.5 μmol/L，同時該化合物對酵母菌、煙曲霉菌、稻瘟病菌、黃萎菌和黃色鐮刀菌等真菌均表現(xiàn)出廣譜的抑制作用，其IC50值均低于20.0 μg/mL[50]。Yun等從海洋真菌Chrysosporiumsynchronum中得到2-O-(α-D-mannopyranosyl-5-hydroxy-3-Chloroben-zylalcoho，該化合物具有很強(qiáng)的清除DPPH自由基抗氧化活性，其IC50值為4.7 μmol/L[51]。Wang等從海洋真菌曲麗穗霉SpicariaelegansKLA-03中分離到含氯新化合物trichodermamide B，該化合物對銅綠假單胞菌Pseudomonasaeruginosa和大腸桿菌Escherichiacoli均有抑制作用，其IC50值分別為0.038和0.767 mmol/L[52]。

圖3　真菌來源的鹵化天然產(chǎn)物

3　其它微生物來源的天然鹵代產(chǎn)物

除了放線菌和真菌之外，人們還從一些稀有甚至是致病菌種發(fā)現(xiàn)了一系列活性鹵化天然產(chǎn)物，如Liu從Pseudomonassp.No.2663中的FR901464發(fā)現(xiàn)一種新的抗腫瘤化合物spliceostatin B 進(jìn)行分離純化得到單體化合物，該化合物能明顯提高病毒DNA SV40啟動子轉(zhuǎn)錄活性，且對小鼠和人腫瘤細(xì)胞具有較強(qiáng)的抑制作用[53]。Funakoshi等從Amycolatopsissp.中發(fā)現(xiàn)新化合物epoxyquinomicins A，該化合物對革蘭氏陽性菌具有較好的抗菌活性[54]。Shaala等從藍(lán)細(xì)菌Lyngbyamajuscula中分離到Malyngamides類新化合物Malyngamides 4，該化合物具有與已知化合物Malyngamides相似的蝦毒性[55]。Orfali等從藍(lán)細(xì)菌Lyngbyamajuscula中發(fā)現(xiàn)Malyngamides R結(jié)構(gòu)類似物isomalyngamides A和B[56]。 Hendtik 等從藍(lán)細(xì)菌Lyngbyasp.中發(fā)現(xiàn)大環(huán)內(nèi)酯苷類化合物lyngbyaloside B，該化合物對LoVo細(xì)胞有抑制作用，其IC50值約為15 μmol/L[57]。Thomas等從藍(lán)細(xì)菌Phormidiumsp.中分離到大環(huán)內(nèi)酯類鹵代物phormidolide，該化合物對鹽水蝦具有高毒性，其IC50值為1.5 μmol/L[58]。

4　展望

鑒于微生物來源鹵化天然產(chǎn)物的巨大成藥潛力和人類面臨的耐藥菌的重大威脅，從微生物鹵化天然產(chǎn)物中發(fā)現(xiàn)新抗生素是人們應(yīng)對“超級菌”的一個有效策略。然而，常規(guī)手段的產(chǎn)物分離不可避免會遇到“重復(fù)發(fā)現(xiàn)”的難題。如何破解這個難題，是抗生素開發(fā)研究人員面臨的重要考驗。以基因組學(xué)、轉(zhuǎn)錄組、代謝組學(xué)等為代表組學(xué)技術(shù)和現(xiàn)代分析測試技術(shù)進(jìn)步為人們提供了有力的武器。研究者可通過次級代謝合成或修飾基因篩選(尤其是鹵化酶基因篩選)從大量的分離菌株中篩選出潛力菌株，結(jié)合次級代謝基因表達(dá)水平分析優(yōu)化出鹵化產(chǎn)物高效合成的發(fā)酵條件，在此基礎(chǔ)結(jié)合高分辨質(zhì)譜等手段對次級代謝產(chǎn)物譜進(jìn)行分析，最終確定鹵化天然產(chǎn)物生物合成條件，發(fā)酵純化制備并獲得相應(yīng)的產(chǎn)物。本課題組利用這些技術(shù)，從1000余株貴州不同生境來源的分離菌株中確定梵凈山土壤來源的鏈霉菌Streptomycessp.FJS31-2為出發(fā)菌株，通過優(yōu)化表達(dá)譜分析示蹤鹵化產(chǎn)物合成，最終獲得新型抗耐甲氧西林金黃色葡萄球菌的鹵化二型聚酮類抗生素zunyimycin A并鑒定了其生物合成基因簇[39]。這表明，只要手段得當(dāng)，通過不同培養(yǎng)條件及外界刺激等，研究者發(fā)現(xiàn)更多結(jié)構(gòu)多樣及復(fù)雜的新型活性鹵化產(chǎn)物，為新藥開發(fā)提供先導(dǎo)化合物還是切實可行。

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[收稿2016-06-05;修回2016-07-08]

(編輯：王福軍)

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.

國家自然科學(xué)基金資助項目(NO：31160004)。

岳昌武，男，博士，副研究員，碩士生導(dǎo)師，研究方向：微生物天然產(chǎn)物生物合成，E-mail:changwuyue@126.com。

Q93

A

1000-2715(2016)04-0435-06