Design, Synthesis, and Biological Evaluation of the Quorum-Sensing Inhibitors of Pseudomonas aeruginosa PAO1

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.