Garrett Oscar, Whalen Kristen E
Department of Biology, Haverford College, Haverford, PA, United States.
Front Microbiol. 2023 Oct 6;14:1266972. doi: 10.3389/fmicb.2023.1266972. eCollection 2023.
Interactions between marine phytoplankton, viruses, and bacteria drive biogeochemical cycling, shape marine trophic structures, and impact global climate. Microbially produced compounds have emerged as key players in influencing eukaryotic organismal physiology, and in turn, remodel microbial community structure. This work aimed to reveal the molecular mechanism by which the bacterial quorum sensing molecule 2-heptyl-4-quinolone (HHQ), produced by the marine gammaproteobacterium spp., arrests cell division and confers protection from virus-induced mortality in the bloom-forming coccolithophore . Previous work has established alkylquinolones as inhibitors of dihydroorotate dehydrogenase (DHODH), a fundamental enzyme catalyzing the fourth step in pyrimidine biosynthesis and a potential antiviral drug target. An N-terminally truncated version of DHODH was heterologously expressed in , purified, and kinetically characterized. Here, we show HHQ is a potent inhibitor (K of 2.3 nM) of DHODH. cells exposed to brequinar, the canonical human DHODH inhibitor, experienced immediate, yet reversible cellular arrest, an effect which mirrors HHQ-induced cellular stasis previously observed. However, brequinar treatment lacked other notable effects observed in HHQ-exposed including significant changes in cell size, chlorophyll fluorescence, and protection from virus-induced lysis, indicating HHQ has additional as yet undiscovered physiological targets. Together, these results suggest a novel and intricate role of bacterial quorum sensing molecules in tripartite interdomain interactions in marine ecosystems, opening new avenues for exploring the role of microbial chemical signaling in algal bloom regulation and host-pathogen dynamics.
海洋浮游植物、病毒和细菌之间的相互作用驱动着生物地球化学循环，塑造海洋营养结构，并影响全球气候。微生物产生的化合物已成为影响真核生物生理机能的关键因素，进而重塑微生物群落结构。这项研究旨在揭示海洋γ-变形菌属产生的细菌群体感应分子2-庚基-4-喹诺酮（HHQ）阻止细胞分裂并保护形成水华的颗石藻免受病毒诱导死亡的分子机制。此前的研究已证实烷基喹诺酮是二氢乳清酸脱氢酶（DHODH）的抑制剂，DHODH是催化嘧啶生物合成第四步的一种基本酶，也是一个潜在的抗病毒药物靶点。将一个N端截短的DHODH在（此处原文缺失相关宿主信息）中进行异源表达、纯化并进行动力学表征。在这里，我们表明HHQ是DHODH的一种强效抑制剂（K为2.3 nM）。暴露于经典人类DHODH抑制剂布喹那的（此处原文缺失相关细胞信息）细胞经历了立即但可逆的细胞停滞，这一效应与之前观察到的HHQ诱导的细胞停滞相似。然而，布喹那处理缺乏在暴露于HHQ的（此处原文缺失相关细胞信息）中观察到的其他显著效应，包括细胞大小、叶绿素荧光的显著变化以及免受病毒诱导裂解的保护作用，这表明HHQ还有尚未发现的其他生理靶点。总之，这些结果表明细菌群体感应分子在海洋生态系统的三方域间相互作用中具有新颖而复杂的作用，为探索微生物化学信号在藻华调控和宿主-病原体动态中的作用开辟了新途径。
