Ding Ling, Zhang Sheng-Da, Haidar Ahmad Kasem, Bajimaya Manila, Guo Yaojie, Larsen Thomas Ostenfeld, Gram Lone
Department of Biotechnology and Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark.
Front Chem. 2021 Nov 12;9:772858. doi: 10.3389/fchem.2021.772858. eCollection 2021.
New infectious diseases and increase in drug-resistant microbial pathogens emphasize the need for antibiotics with novel mode-of-action. Tetramates represented by fungi-derived tenuazonic acid and bacterial polycyclic tetramate macrolactams (PTMs) are an important family of natural products with a broad spectrum of antimicrobial activities. Despite their potential application as new antibiotics, it remains unknown how PTMs function. In this study, genomic mining revealed that PTM biosynthetic gene clusters (BGCs) are widespread in both Gram-positive and Gram-negative bacteria, and we investigated a sponge endosymbiont harboring a potential PTM-BGC. Xanthobaccin A that previously has only been isolated from a Gram-negative bacterium was obtained after a scale-up fermentation, isolation, and structure elucidation through mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy. Xanthobaccin A as well as two previously reported tetramates, equisetin and ikarugamycin, exhibited antibacterial activities against . In addition, these three tetramates were for the first time to be confirmed as metallophores and the stoichiometry of the complexes were shown to be Fe(III)(equisetin)/Fe(III)(equisetin) and Fe(III)(ikarugamycin), respectively. Meanwhile, we found that all three tetramates could reduce ferric into ferrous iron, which triggers the Fenton chemistry reaction. Their antibacterial activity was reduced by adding the radical scavenger, vitamin C. Altogether, our work demonstrates that equisetin and PTMs can act as metallophores and their antimicrobial mechanism is possibly mediated through Fenton chemistry.
新出现的传染病以及耐药微生物病原体的增加凸显了开发具有新型作用模式抗生素的必要性。以真菌来源的细交链孢菌酮酸和细菌多环四元酸大环内酯（PTMs）为代表的四元酸是一类具有广泛抗菌活性的重要天然产物家族。尽管它们作为新型抗生素具有潜在应用价值，但PTMs的作用机制仍不清楚。在本研究中，基因组挖掘显示PTM生物合成基因簇（BGCs）在革兰氏阳性菌和革兰氏阴性菌中广泛存在，并且我们研究了一种携带潜在PTM-BGC的海绵共生菌。通过大规模发酵、分离，并利用质谱和核磁共振（NMR）光谱进行结构解析后，获得了之前仅从革兰氏阴性菌中分离出的黄杆菌素A。黄杆菌素A以及之前报道的两种四元酸，木贼菌素和ikarugamycin，均表现出对……的抗菌活性。此外，这三种四元酸首次被确认为金属载体，并且复合物的化学计量比分别显示为Fe(III)(木贼菌素)/Fe(III)(木贼菌素)和Fe(III)(ikarugamycin)。同时，我们发现所有这三种四元酸都能将三价铁还原为二价铁，从而引发芬顿化学反应。添加自由基清除剂维生素C后，它们的抗菌活性降低。总之，我们的工作表明木贼菌素和PTMs可以作为金属载体，并且它们的抗菌机制可能是通过芬顿化学介导的。
