Mishra Biswajit, Khader Rajamohammed, Felix Lewis Oscar, Frate Marissa, Mylonakis Eleftherios, Meschwitz Susan, Fuchs Beth Burgwyn
Division of Infectious Diseases, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI, United States.
Department of Chemistry, Salve Regina University, Newport, RI, United States.
Front Microbiol. 2021 Oct 5;12:723133. doi: 10.3389/fmicb.2021.723133. eCollection 2021.
Antimicrobial compounds can combat microbes through modulating host immune defense, inhibiting bacteria survival and growth, or through impeding or inhibiting virulence factors. In the present study, a panel of substituted diphenyl amide compounds previously found to disrupt bacterial quorum sensing were investigated and several were found to promote survival in the model when provided therapeutically to treat a Gram-positive bacterial infection from methicillin-resistant strain MW2. Out of 21 tested compounds, -4-Methoxyphenyl-3-(4-methoxyphenyl)-propanamide (AMI 82B) was the most potent at disrupting . virulence and promoted 50% larvae survival at 120 and 96 h when delivered at 0.5 and 5 mg/Kg, respectively, compared to untreated controls ( < 0.0001). AMI 82B did not exhibit . toxicity ( > 144 h) at a delivery concentration up to 5 mg/Kg. Further assessment with mammalian cells suggest AMI 82B hemolytic effects against erythrocytes has an greater than the highest tested concentration of 64 μg/mL. Against HepG2 hepatic cells, AMI 82B demonstrated an greater than 64 μg/mL. AMI 82B lacked direct bacteria inhibition with a minimal inhibitory concentration that exceeds 64 μg/mL and no significant reduction in . growth curve at the same concentration. Assessment via qPCR revealed that AMI 82B significantly depressed quorum sensing genes , , and ( < 0.05). Thus, AMI 82B therapeutic effect against . in the . infection model is likely an influence on bacterial quorum sensing driven virulence factors and provides an interesting hit compound for this medically important pathogen.
抗菌化合物可通过调节宿主免疫防御、抑制细菌存活和生长，或通过阻碍或抑制毒力因子来对抗微生物。在本研究中，对一组先前发现可破坏细菌群体感应的取代二苯甲酰胺化合物进行了研究，发现其中几种化合物在用于治疗耐甲氧西林菌株MW2引起的革兰氏阳性细菌感染时，能促进模型中的存活率。在21种测试化合物中，-4-甲氧基苯基-3-(4-甲氧基苯基)-丙酰胺（AMI 82B）在破坏毒力方面最为有效，与未处理的对照组相比（P < 0.0001），分别以0.5和5 mg/Kg的剂量给药时，在120小时和96小时时可促进50%的幼虫存活。AMI 82B在高达5 mg/Kg的给药浓度下未表现出毒性（LD50 > 144小时）。对哺乳动物细胞的进一步评估表明，AMI 82B对红细胞的溶血作用的LD50大于最高测试浓度64 μg/mL。对于HepG2肝细胞，AMI 82B的LD50大于64 μg/mL。AMI 82B缺乏直接的细菌抑制作用，其最小抑菌浓度超过64 μg/mL，并且在相同浓度下生长曲线没有显著降低。通过qPCR评估发现，AMI 82B显著抑制群体感应基因luxS、luxR和pfs（P < 0.05）。因此，AMI 82B在幼虫感染模型中对金黄色葡萄球菌的治疗作用可能是对细菌群体感应驱动的毒力因子的影响，并为这种医学上重要的病原体提供了一种有趣的命中化合物。
