Antibiotic “megacluster” discovery provides new strategy to fight superbugs

抗生素“超级基因簇”的发现为对抗超级细菌提供了新策略

Antibiotic resistance has loomed over humans since the moment we started using antibiotics. In the 20th century, the drugs downgraded potentially life-threatening bacterial infections to mere inconveniences—a miracle of modern medicine, it seemed. But the drugs aren’t really a human invention; we mostly swiped them from microbes, which have been locked in an arms race with each other for centuries. 自从人类开始使用抗生素的那一刻起，抗生素耐药性就一直笼罩着我们。在20世纪，这些药物将可能危及生命的细菌感染降级为仅仅是“不便之处”——这看起来是现代医学的一个奇迹。但这些药物并非人类的真正发明；我们大多是从微生物那里“借用”来的，而微生物之间几个世纪以来一直处于军备竞赛之中。

Microbial evolution has crafted both deadly molecules and clever tricks to dodge death as the wee organisms endlessly battle over turf and resources. More than 80 percent of the antibiotics used in clinics today are based on those turf-war weapons, which scientists refer to as “natural products.” For decades, humans mined antibiotic molecules from microbes and tweaked them to develop new drugs, staying ahead of evolution’s cunning countermeasures. 在这些微小生物为争夺地盘和资源而无休止地战斗时，微生物进化既创造了致命的分子，也演化出了躲避死亡的巧妙伎俩。如今临床使用的抗生素中，超过80%是基于这些“地盘争夺战”中的武器，科学家将其称为“天然产物”。几十年来，人类从微生物中挖掘抗生素分子并对其进行改良以开发新药，从而在进化的狡猾对策面前保持领先。

But in recent times, new natural products have been harder to find, and the pipeline of new antibiotics has slowed to a trickle. Meanwhile, existing antibiotics have been overused, and resistance has mounted to critical levels. Most antibiotics are single bioactive molecules, and some can be thwarted with single mutations. While the current situation is dire, a study in Nature this week reports a compelling discovery that not only points to a potentially new antibiotic regimen, but also an entirely new strategy to once again get ahead in the microbial arms race. 但近年来，新的天然产物越来越难发现，新抗生素的研发管线已减缓至涓涓细流。与此同时，现有抗生素被过度使用，耐药性已上升到临界水平。大多数抗生素是单一的生物活性分子，有些可以通过单一突变被抵御。尽管目前形势严峻，但本周发表在《自然》杂志上的一项研究报告了一项引人注目的发现，它不仅指向了一种潜在的新型抗生素疗法，还提供了一种全新的策略，让我们能在微生物军备竞赛中再次占据上风。

Exciting find

令人兴奋的发现

The study, led by biomedical researcher Eric Brown at McMaster University in Ontario, Canada, reports the discovery of a large block of genes—dubbed a “megacluster”—that codes for four molecules that appear to work in concert to derail a single essential metabolic pathway. It’s “an exciting advance in efforts to restock the antibiotic arsenal,” Steven Rutherford, a microbial sciences expert at Genentech, wrote in an accompanying commentary piece in Nature. “More broadly, the study provides a road map showing how genome mining can be used to identify new antibacterial natural products and strategies for using them.” 这项由加拿大安大略省麦克马斯特大学生物医学研究员埃里克·布朗（Eric Brown）领导的研究，报告发现了一个巨大的基因块——被称为“超级基因簇”（megacluster）——它编码了四种分子，这些分子似乎协同工作，破坏了一条单一的必需代谢途径。基因泰克（Genentech）的微生物科学专家史蒂文·卢瑟福（Steven Rutherford）在《自然》杂志随附的评论文章中写道：“这是充实抗生素武器库努力中的一项令人兴奋的进展。更广泛地说，这项研究提供了一张路线图，展示了如何利用基因组挖掘来识别新的抗菌天然产物及其使用策略。”

The pathway the megacluster’s products attack is one for making biotin, also known as vitamin B7. The nutrient is required for growth and virulence in many human pathogens, and, more specifically, it’s a cofactor that critical metabolic enzymes need to work properly. Some bacteria can scavenge biotin from their surroundings, but it’s generally scarce, and bacteria contain evolutionarily conserved pathways to make it themselves. 该超级基因簇产物攻击的途径是生物素（也称为维生素B7）的合成途径。这种营养物质是许多人类病原体生长和致病所必需的，更具体地说，它是关键代谢酶正常工作所需的辅因子。一些细菌可以从环境中获取生物素，但这种物质通常很稀缺，因此细菌体内进化出了保守的途径来自行合成它。

Brown and his colleagues interestingly found the biotin-targeting megacluster in Streptomyces species, which are very well studied. Streptomyces are bacteria that live in soil and are known as gold mines for antibiotic molecule discovery. Many natural products have already been extracted from them, including the antibiotic streptomycin, an essential medicine discovered in the 1940s. Despite this, the megacluster has been overlooked until now, possibly in part because bacteria in labs are often grown in nutrient-rich media. 布朗及其同事有趣地在链霉菌（Streptomyces）中发现了这个针对生物素的超级基因簇，而链霉菌是研究非常透彻的物种。链霉菌是生活在土壤中的细菌，被誉为抗生素分子发现的“金矿”。许多天然产物已经从中提取出来，包括20世纪40年代发现的必需药物——链霉素。尽管如此，这个超级基因簇直到现在才被发现，部分原因可能是实验室中的细菌通常在营养丰富的培养基中生长。

Fresh strategy

全新策略

Also, when researchers are looking for new antibiotics in bacterial genomes, they scan for biosynthetic gene clusters (BGCs) that could be responsible for producing single molecules. But Brown’s team identified a cluster of four clusters—the megacluster—that produces not just one, but four molecules that work in different ways to trip up the biotin pathway. Careful study revealed that three of the clusters produce antibiotics molecules—stravidins, acidomycins, dapamycins—that each thwart a different enzyme in the biotin biosynthesis pathway. 此外，当研究人员在细菌基因组中寻找新抗生素时，他们通常扫描的是负责产生单一分子的生物合成基因簇（BGCs）。但布朗的团队识别出了一个由四个基因簇组成的“超级基因簇”，它产生的不是一个，而是四个分子，它们以不同的方式协同阻断生物素途径。仔细研究发现，其中三个基因簇产生的抗生素分子——stravidins、acidomycins和dapamycins——分别阻断了生物素生物合成途径中不同的酶。

The remaining fourth cluster produces 2-methyl-7-keto-8-aminopelargonic acid, or α-Me-KAPA, which appears to be a dummy molecule that takes the place of a biotin precursor, basically hijacking the pathway to yield a useless biotin lookalike. Further, the megacluster is flanked on both sides for the code to make streptavidin, a protein known to take up and sequester biotin. 剩下的第四个基因簇产生2-甲基-7-酮-8-氨基壬二酸（α-Me-KAPA），这似乎是一个“诱饵分子”，它取代了生物素的前体，从本质上劫持了该途径，从而产生了一种无用的生物素类似物。此外，该超级基因簇的两侧还带有编码链霉亲和素（streptavidin）的基因，这种蛋白质已知能结合并隔离生物素。

In all, the megacluster provides a sophisticated siege on an essential pathway in many bacteria, including Streptomyces’ foes. Experiments in test tubes and in mice confirmed that the megacluster’s products could kill off various bacteria and were more potent when used in combination. As antibiotic resistance has increased in clinics, doctors and researchers have had to test which combinations of drugs might be able to boost efficacy. But, as Rutherford noted in his commentary, “The discovery of a natural megacluster that encodes the production of synergistic biotin-synthesis inhibitors suggests that evolution has already identified effective combinations of antibacterials that act through distinct mechanisms.” 总而言之，这个超级基因簇对许多细菌（包括链霉菌的敌人）的必需代谢途径实施了复杂的“围攻”。试管和小白鼠实验证实，该超级基因簇的产物可以杀死多种细菌，且联合使用时效力更强。随着临床抗生素耐药性的增加，医生和研究人员不得不测试哪些药物组合能够提高疗效。但正如卢瑟福在评论中所指出的：“发现一个编码协同生物素合成抑制剂的天然超级基因簇，表明进化早已识别出了通过不同机制起作用的有效抗菌药物组合。”

Moreover, such evolved synergistic systems may be harder for microbes to develop countermeasures against, thus they may stave off resistance. Rutherford is careful to note that there are many big steps between this discovery and having a new antibiotic regimen in clinics. That includes more basic research, optimization of the molecules for delivery in humans, as well as pricy and lengthy safety and efficacy clinical trials. Still, moving from scanning for individual BGCs to “megaclusters” is a fresh strategy that could reinvigorate natural product development. 此外，微生物可能更难针对这种进化出的协同系统产生对策，因此它们或许能延缓耐药性的产生。卢瑟福谨慎地指出，从这一发现到临床应用新型抗生素疗法之间还有许多重大步骤。这包括更多的基础研究、针对人体给药的分子优化，以及昂贵且漫长的安全性和有效性临床试验。尽管如此，从扫描单个BGC转向“超级基因簇”是一种全新的策略，可能会重新激发天然产物的开发。

“The architecture of the anti-biotin megacluster provides a paradigm for naturally evolved combination therapies, supporting a shift in antibiotic discovery from isolating individual hits to reconstructing native synergistic systems,” Brown and his colleagues conclude. “As genome-mining methods advance, the identification of similar megaclusters may reveal new paths for overcoming antibiotic resistance.” “抗生物素超级基因簇的架构为自然进化的联合疗法提供了一个范式，支持抗生素发现从分离单个药物靶点向重建天然协同系统转变，”布朗及其同事总结道。“随着基因组挖掘方法的进步，识别类似的超级基因簇可能会揭示克服抗生素耐药性的新途径。”