In situ activation and heterologous production of a cryptic lantibiotic from a plant-ant derived Saccharopolyspora species
In situ activation and heterologous production of a cryptic lantibiotic from a plant-ant derived Saccharopolyspora species
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来自植物蚂蚁来源的糖多孢菌物种的隐性羊毛硫抗生素的原位激活和异源生产
DOI：
10.1101/733808
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Vikeli E
中科院分区：
文献类型：
--
作者：
Vikeli E
大多数临床抗生素是从至少60年前发现的放线菌天然产物中提取的。然而，已知化合物的反复重新发现导致制药行业在很大程度上放弃了微生物天然产物（NPs）作为新化学多样性的来源。基因组测序的最新进展表明，这些生物有可能产生比以前认为的更多的NPs。通过菌株的遗传操作、化学遗传学的应用或微生物共培养来解锁NP生物合成的方法已经导致了新的抗菌化合物的鉴定。与此同时，对共同进化生态位的深入探索，如昆虫-微生物防御共生，已经揭示了这些是化学新事物的丰富来源。在这里，我们报道了新的蓝肽抗生素kyamicin，它是通过激活在蚁类植物Vachellia drepanolobium的专性巢居蚂蚁Tetraponera penzigi中发现的一个由基因组挖掘鉴定的隐性生物合成基因簇而产生的。该沉默基因簇的转录激活是通过在组成启动子控制下通路特异性激活子的异位表达实现的。随后，建立了一个异种生产平台，纯化了kyamicin，进行了结构表征和生物活性测定。这一策略也成功地用于从其他属中生产蓝硫肽，为发现在实验室条件下未检测到的或自然界新发现的蓝硫肽的合成异源表达平台铺平了道路。由于难以充分利用微生物的生物合成潜力，发现新型抗生素以应对日益严重的抗菌素耐药性威胁受到阻碍。开发新的工具来解锁隐菌天然产物的生物合成将大大增加天然产物支架的曲目。在这里，我们报道了一种通路特异性阳性调节因子的异位表达策略，该策略可以快速应用于激活隐肽生物合成基因簇的生物合成。这使得直接从原生宿主和通过异源表达发现了一种新的硫肽抗生素。
Most clinical antibiotics are derived from actinomycete natural products discovered at least 60 years ago. However, the repeated rediscovery of known compounds led the pharmaceutical industry to largely discard microbial natural products (NPs) as a source of new chemical diversity. Recent advances in genome sequencing have revealed that these organisms have the potential to make many more NPs than previously thought. Approaches to unlock NP biosynthesis by genetic manipulation of strains, by the application of chemical genetics, or by microbial cocultivation have resulted in the identification of new antibacterial compounds. Concomitantly, intensive exploration of coevolved ecological niches, such as insect-microbe defensive symbioses, has revealed these to be a rich source of chemical novelty. Here, we report the new lanthipeptide antibiotic kyamicin, which was generated through the activation of a cryptic biosynthetic gene cluster identified by genome miningSaccharopolysporaspecies found in the obligate domatium-dwelling ant Tetraponera penzigi of the ant plant Vachellia drepanolobium. Transcriptional activation of this silent gene cluster was achieved by ectopic expression of a pathway-specific activator under the control of a constitutive promoter. Subsequently, a heterologous production platform was developed which enabled the purification of kyamicin for structural characterization and bioactivity determination. This strategy was also successful for the production of lantibiotics from other genera, paving the way for a synthetic heterologous expression platform for the discovery of lanthipeptides that are not detected under laboratory conditions or that are new to nature.IMPORTANCEThe discovery of novel antibiotics to tackle the growing threat of antimicrobial resistance is impeded by difficulties in accessing the full biosynthetic potential of microorganisms. The development of new tools to unlock the biosynthesis of cryptic bacterial natural products will greatly increase the repertoire of natural product scaffolds. Here, we report a strategy for the ectopic expression of pathway-specific positive regulators that can be rapidly applied to activate the biosynthesis of cryptic lanthipeptide biosynthetic gene clusters. This allowed the discovery of a new lanthipeptide antibiotic directly from the native host and via heterologous expression.
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影响因子：
3.4
作者：
Seipke, Ryan F.;Barke, Joerg;Heavens, Darren;Yu, Douglas W.;Hutchings, Matthew I.
通讯作者：
Hutchings, Matthew I.
影响因子：
15
作者：
Odette L. Shotwell;F. Stodola;William R. Michael;L. A. Lindenfelser;R. G. Dworschack;T. G. Pridham
通讯作者：
T. G. Pridham
影响因子：
46.2
作者：
Ethan B. Van Arnam;C. Currie;J. Clardy
通讯作者：
Ethan B. Van Arnam;C. Currie;J. Clardy
影响因子：
3.4
作者：
Iwamoto, Kunihiko;Hayakawa, Tomohiro;Kobayashi, Toshihide
通讯作者：
Kobayashi, Toshihide
影响因子：
11.9
作者：
Arnison PG;Bibb MJ;Bierbaum G;Bowers AA;Bugni TS;Bulaj G;Camarero JA;Campopiano DJ;Challis GL;Clardy J;Cotter PD;Craik DJ;Dawson M;Dittmann E;Donadio S;Dorrestein PC;Entian KD;Fischbach MA;Garavelli JS;Göransson U;Gruber CW;Haft DH;Hemscheidt TK;Hertweck C;Hill C;Horswill AR;Jaspars M;Kelly WL;Klinman JP;Kuipers OP;Link AJ;Liu W;Marahiel MA;Mitchell DA;Moll GN;Moore BS;Müller R;Nair SK;Nes IF;Norris GE;Olivera BM;Onaka H;Patchett ML;Piel J;Reaney MJ;Rebuffat S;Ross RP;Sahl HG;Schmidt EW;Selsted ME;Severinov K;Shen B;Sivonen K;Smith L;Stein T;Süssmuth RD;Tagg JR;Tang GL;Truman AW;Vederas JC;Walsh CT;Walton JD;Wenzel SC;Willey JM;van der Donk WA
通讯作者：
van der Donk WA