National Engineering Research Center for the Emergency Drug, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
School of Pharmaceutical Sciences, Jilin University, Changchun 130021, China.
Molecules. 2024 May 8;29(10):2211. doi: 10.3390/molecules29102211.
Due to the resistance of Gram-negative bacteria PAO1 to most clinically relevant antimicrobials, the use of traditional antibiotic treatments in hospitals is challenging. The formation of biofilms, which is regulated by the quorum-sensing (QS) system of (PA), is an important cause of drug resistance. There are three main QS systems in : the system, the system, and the system. The inhibitors of the system are the most studied. Previously, the compound was found to have a certain inhibitory effect on the system when screened. In this study, twenty-four compounds were designed and synthesized by modifying the Linker and Rings of . Using CV026 as a reporter strain, this study first assessed the inhibitory effects of new compounds against QS, and their SAR was investigated. Then, based on the SAR analysis of compound derivatives, the parent core of AOZ-1 was replaced to explore the structural diversity. Then, nine new compounds were designed and synthesized with a new nucleus core component of 3-amino-tetrahydro-l,3-oxazin-2-one. The compound (IC = 91.55 ± 3.35 µM) was found to inhibit the QS of CV026. Its inhibitory effect on CV026 was better than that of compound (IC > 200 µM). Furthermore, biofilm formation is one of the important causes of PAO1 resistance. In this study, it was found that compound with a new nucleus core component of 3-amino-tetrahydro-l,3-oxazin-2-one, had the highest biofilm inhibition rate (40.44%). The compound has a certain inhibitory effect on the production of PAO1 virulence factors (pyocyanin, rhamnolipid, and elastase) and swarming. When the concentration of compound was 162.5 µM, the inhibition rates of pyocyanin, rhamnolipid, and elastase were 22.48%, 6.13%, and 22.67%, respectively. In vivo, the lifetime of wildtype N2 infected with PAO1 was markedly extended by the new parent nucleus . This study also performed cytotoxicity experiments and in vivo pharmacokinetics experiments on the compound . In conclusion, this study identified a compound, , with a new nucleus core component of 3-amino-tetrahydro-l,3-oxazin-2-one, which is a potential agent for treating PAO1 that is resistant to antibiotics and offers a way to discover novel antibacterial medications.
由于革兰氏阴性菌 PAO1 对大多数临床相关抗菌药物具有抗性，因此医院使用传统抗生素治疗具有挑战性。生物膜的形成受（PA）群体感应（QS）系统的调节，是耐药性的一个重要原因。有三个主要的 QS 系统：系统、系统和系统。系统的抑制剂研究最多。以前，在筛选时发现化合物是对系统具有一定抑制作用。在这项研究中，通过修饰的连接子和环，设计并合成了 24 种化合物。使用 CV026 作为报告菌株，本研究首先评估了新化合物对 QS 的抑制作用，并对其 SAR 进行了研究。然后，基于化合物衍生物的 SAR 分析，用 AOZ-1 的母核取代来探索结构多样性。然后，设计并合成了 9 种具有新的核芯成分 3-氨基四氢-1,3-恶嗪-2-酮的新型化合物。发现化合物（IC = 91.55 ± 3.35 µM）抑制 CV026 的 QS。其对 CV026 的抑制作用优于化合物（IC > 200 µM）。此外，生物膜形成是 PAO1 耐药的重要原因之一。在这项研究中，发现具有新核芯成分 3-氨基四氢-1,3-恶嗪-2-酮的化合物对生物膜的抑制率最高（40.44%）。该化合物对 PAO1 毒力因子（绿脓菌素、鼠李糖脂和弹性蛋白酶）的产生和群集有一定的抑制作用。当化合物浓度为 162.5 µM 时，对绿脓菌素、鼠李糖脂和弹性蛋白酶的抑制率分别为 22.48%、6.13%和 22.67%。在体内，新型母体核对野生型 N2 感染的 PAO1 的寿命明显延长。本研究还对化合物进行了细胞毒性实验和体内药代动力学实验。总之，本研究发现了一种具有新核芯成分 3-氨基四氢-1,3-恶嗪-2-酮的化合物，它是一种治疗对抗生素耐药的 PAO1 的潜在药物，为发现新型抗菌药物提供了一种途径。
