Sieniawska Elwira, Sawicki Rafal, Truszkiewicz Wieslaw, Marchev Andrey S, Georgiev Milen I
Medical University of Lublin, Chair and Department of Pharmacognosy, Lublin, Poland
Medical University of Lublin, Chair and Department of Biochemistry and Biotechnology, Lublin, Poland.
mSystems. 2021 May 4;6(3):e00097-21. doi: 10.1128/mSystems.00097-21.
developed efficient adaptation mechanisms in response to different environmental conditions. This resulted in the ability to survive in human macrophages and in resistance to numerous antibiotics. To get insight into bacterial responses to potent antimycobacterial natural compounds, we tested how usnic acid, a lichen-derived secondary metabolite, would influence mycobacteria at transcriptomic and metabolomic levels. The analysis of expression of sigma factors revealed a profound impact of usnic acid on one of the primary genetic regulatory systems of Combined liquid chromatography-mass spectrometry and nuclear magnetic resonance analyses allowed us to observe the perturbations in metabolic pathways, as well as in lipid composition, which took place within 24 h of exposure. Early bacterial response was related to redox homeostasis, lipid synthesis, and nucleic acid repair. Usnic acid treatment provoked disturbances of redox state in mycobacterial cells and increased production of structural elements of the cell wall and cell membrane. In addition, to increase the number of molecules related to restoration of redox balance, the rearrangements of the cell envelope were the first defense mechanisms observed under usnic acid treatment. The evaluation of mechanisms of mycobacterial response to natural products has been barely studied. However, it might be helpful to reveal bacterial adaptation strategies, which are eventually crucial for the discovery of new drug targets and, hence, understanding the resistance mechanisms. This study showed that the first-line mycobacterial defense against usnic acid, a potent antimicrobial agent, is the remodeling of the cell envelope and restoring redox homeostasis. Transcriptomic data correlated with metabolomics analysis. The observed metabolic changes appeared similar to those exerted by antibiotics.
细菌进化出了高效的适应机制以应对不同的环境条件。这使其具备了在人类巨噬细胞中存活以及对多种抗生素产生抗性的能力。为深入了解细菌对强效抗分枝杆菌天然化合物的反应，我们测试了地衣衍生的次生代谢产物松萝酸如何在转录组和代谢组水平上影响分枝杆菌。对σ因子表达的分析揭示了松萝酸对主要遗传调控系统之一的深远影响。液相色谱 - 质谱联用和核磁共振分析使我们能够观察到在暴露24小时内代谢途径以及脂质组成发生的扰动。细菌的早期反应与氧化还原稳态、脂质合成和核酸修复有关。松萝酸处理引发了分枝杆菌细胞内氧化还原状态的紊乱，并增加了细胞壁和细胞膜结构成分的产生。此外，为增加与恢复氧化还原平衡相关的分子数量，细胞膜的重排是在松萝酸处理下观察到的首要防御机制。对分枝杆菌对天然产物反应机制的评估研究甚少。然而，这可能有助于揭示细菌的适应策略，而这最终对于发现新的药物靶点以及理解耐药机制至关重要。本研究表明，分枝杆菌对强效抗菌剂松萝酸的一线防御是细胞膜重塑和恢复氧化还原稳态。转录组数据与代谢组学分析相关。观察到的代谢变化与抗生素引起的变化相似。
