A marine-derived fatty acid targets the cell membrane of Gram-positive bacteria.
A marine-derived fatty acid targets the cell membrane of Gram-positive bacteria.
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一种海洋衍生的脂肪酸以革兰氏阳性细菌的细胞膜为靶标。
DOI：
10.1128/jb.00310-23
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发表时间：
2023-11-21
影响因子：
3.2
通讯作者：
Whalen, Kristen E.
中科院分区：
文献类型：
--
作者：
Upender, Isha;Yoshida, Olivia;Schrecengost, Anna;Ranson, Hilary;Wu, Qihao;Rowley, David C.;Kishore, Shreya;Cywes, Claire;Miller, Eric L.;Whalen, Kristen E.
抗生素耐药性的快速演变正在减少我们的商业可用抗生素库存。因此，迫切需要具有新作用机制（MoAs）的新抗菌剂。从海洋沉积物细菌Olleya marilimosa中分离的游离脂肪酸（Z）-13-甲基四-4-癸烯酸（（Z）-4C-14：1）显示出对革兰氏阳性病原体的强抑制作用，对哺乳动物细胞的细胞毒性作用最小。在这里，我们应用实验方法的组合来鉴定（Z）-4C-14：1杀死革兰氏阳性细菌枯草芽孢杆菌的机制。使用快速和具有成本效益的细菌细胞学分析（BCP），我们建立了17种抗生素的细胞学特征，代表6大类抗生素MoAs。我们用BCP证明，当（Z）-4C-14：1处理B时，与其他抗生素类别相比，枯草杆菌细胞显示出独特的形态学特征，（Z）-4C-14：1的作用模式与快速作用的抗生素粘杆菌素（特别是在革兰氏阳性细胞中）和达托霉素（两者都通过破坏细胞膜并引起广泛的细胞表面改变来靶向细菌渗透性）具有实质性重叠。进一步确定B.枯草杆菌是（Z）-4C-14：1的靶标，我们使用细胞膜和肽聚糖特异性诊断染料来研究细菌渗透性。我们的研究结果表明，（Z）-4C-14：1通过在革兰氏阳性细菌中形成孔来破坏细胞膜的稳定性，并强调了在海洋环境中开采天然抗生素的重要性。由于药物发现管道中缺乏新的抗生素，加上抗生素耐药性的加速演变，靶向临床重要病原体的抗生素的新来源至关重要。在这里，我们使用细菌细胞学分析，以确定从海洋细菌Olleya marilimosa中分离的单不饱和脂肪酸（Z）-13-甲基四-4-癸烯酸的作用机制，对革兰氏阳性菌具有抗菌作用。发现脂肪酸抗生素通过枯草芽孢杆菌中的孔形成和膜聚集快速使细胞膜不稳定，这表明这种脂肪酸可能是组合使用以增强抗生素敏感性的有前途的佐剂。
The rapid evolution of antibiotic resistance is shrinking our stockpile of commercially available antibiotics. Therefore, new antimicrobials with novel mechanisms of action (MoAs) are desperately needed. The free fatty acid, (Z)-13-methyltetra-4-decenoic acid ((Z)-4C-14:1), isolated from a marine sediment bacterium Olleya marilimosa, displays strong inhibition of Gram-positive pathogens with minimal cytotoxic effects to mammalian cells. Here, we applied a combination of experimental approaches to identify the mechanism by which (Z)-4C-14:1 kills the Gram-positive bacterium Bacillus subtilis. Using quick and cost-effective bacterial cytological profiling (BCP), we established the cytological signatures of 17 antibiotics representing 6 general classes of antibiotic MoAs. We used BCP to demonstrate that while (Z)-4C-14:1-treated B. subtilis cells display unique morphological features compared to other antibiotic classes, (Z)-4C-14:1 mode of action shares substantial overlap with the fast-acting antibiotic colistin specifically in Gram-positive cells and daptomycin, both of which target bacterial permeability by destroying the cell membrane and causing extensive cell surface alterations. To further determine if the cell membrane of B. subtilis was the target of (Z)-4C-14:1, we used cell membrane- and peptidoglycan-specific diagnostic stains to investigate bacterial permeability. Our results indicate that (Z)-4C-14:1 destabilizes the cell membrane by pore formation in Gram-positive bacteria and emphasize the importance of mining the marine environment for naturally occurring antibiotics. With the lack of new antibiotics in the drug discovery pipeline, coupled with accelerated evolution of antibiotic resistance, new sources of antibiotics that target pathogens of clinical importance are paramount. Here, we use bacterial cytological profiling to identify the mechanism of action of the monounsaturated fatty acid (Z)-13-methyltetra-4-decenoic acid isolated from the marine bacterium Olleya marilimosa with antibacterial effects against Gram-positive bacteria. The fatty acid antibiotic was found to rapidly destabilize the cell membrane by pore formation and membrane aggregation in Bacillus subtilis, suggesting that this fatty acid may be a promising adjuvant used in combination to enhance antibiotic sensitivity.
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重要的革兰氏阳性和革兰氏阴性病原体和新型抗生素溶液中抗生素抗性的机制。
DOI：
10.3390/antibiotics10040415
发表时间：
2021-04-10
期刊：
Antibiotics (Basel, Switzerland)
影响因子：
--
作者：
Kakoullis L;Papachristodoulou E;Chra P;Panos G
通讯作者：
Panos G
影响因子：
4.9
作者：
Hess, Donavon J.;Henry-Stanley, Michelle J.;Wells, Carol L.
通讯作者：
Wells, Carol L.
影响因子：
12.3
作者：
Carpenter AE;Jones TR;Lamprecht MR;Clarke C;Kang IH;Friman O;Guertin DA;Chang JH;Lindquist RA;Moffat J;Golland P;Sabatini DM
通讯作者：
Sabatini DM
影响因子：
1.9
作者：
CHRISTIE, WW;BRECHANY, EY;POPOV, S
通讯作者：
POPOV, S
影响因子：
11
作者：
Chase, Alexander B.;Bogdanov, Alexander;Demko, Alyssa M.;Jensen, Paul R.
通讯作者：
Jensen, Paul R.