Department of Biochemistry, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
J Bacteriol. 2024 Mar 21;206(3):e0032523. doi: 10.1128/jb.00325-23. Epub 2024 Feb 14.
are the primary source of bioactive specialized metabolites used in research and medicine, including many antimicrobials. These are presumed to be secreted and function as freely soluble compounds. However, increasing evidence suggests that extracellular vesicles are an alternative secretion system. We assessed environmental and lab-adapted (sporulating filamentous actinomycetes) and found frequent production of antimicrobial vesicles. The molecular cargo included actinomycins, anthracyclines, candicidin, and actinorhodin, reflecting both diverse chemical properties and diverse antibacterial and antifungal activity. The levels of packaged antimicrobials correlated with the level of inhibitory activity of the vesicles, and a strain knocked out for the production of anthracyclines produced vesicles that lacked antimicrobial activity. We demonstrated that antimicrobial containing vesicles achieve direct delivery of the cargo to other microbes. Notably, this delivery via membrane fusion occurred to a broad range of microbes, including pathogenic bacteria and yeast. Vesicle encapsulation offers a broad and permissive packaging and delivery system for antimicrobial specialized metabolites, with important implications for ecology and translation.IMPORTANCEExtracellular vesicle encapsulation changes our picture of how antimicrobial metabolites function in the environment and provides an alternative translational approach for the delivery of antimicrobials. We find many strains are capable of releasing antimicrobial vesicles, and at least four distinct classes of compounds can be packaged, suggesting this is widespread in nature. This is a striking departure from the primary paradigm of the secretion and action of specialized metabolites as soluble compounds. Importantly, the vesicles deliver antimicrobial metabolites directly to other microbes via membrane fusion, including pathogenic bacteria and yeast. This suggests future applications in which lipid-encapsulated natural product antibiotics and antifungals could be used to solve some of the most pressing problems in drug resistance.
是生物活性专用代谢物的主要来源，用于研究和医学，包括许多抗菌药物。这些物质被认为是分泌出来的，作为游离的可溶性化合物发挥作用。然而，越来越多的证据表明，细胞外囊泡是一种替代的分泌系统。我们评估了环境和实验室适应的（产孢子丝状放线菌），发现经常产生抗菌囊泡。分子货物包括放线菌素、蒽环类抗生素、坎地西丁和放线红菌素，反映了多样化的化学性质以及多样化的抗菌和抗真菌活性。包装的抗菌药物的水平与囊泡的抑制活性水平相关，并且一种敲除蒽环类抗生素产生的菌株产生了缺乏抗菌活性的囊泡。我们证明了含有抗菌药物的囊泡能够将货物直接递送到其他微生物。值得注意的是，这种通过膜融合的递呈发生在广泛的微生物中，包括致病菌和酵母。囊泡包封提供了一个广泛而许可的包装和递呈抗菌专用代谢物的系统，对生态学和转化具有重要意义。
重要性细胞外囊泡的包封改变了我们对环境中抗菌代谢物如何发挥作用的认识，并为抗菌药物的递呈提供了一种替代的转化方法。我们发现许多 菌株能够释放抗菌囊泡，至少有四种不同类别的化合物可以被包装，这表明这在自然界中很普遍。这与专用代谢物作为可溶性化合物分泌和作用的主要范式有很大的不同。重要的是，囊泡通过膜融合将抗菌代谢物直接递送到其他微生物，包括致病菌和酵母。这表明，在未来的应用中，可以使用脂质包裹的天然产物抗生素和抗真菌药物来解决一些最紧迫的耐药问题。
