There is a significant need to combat the growing challenge of antibacterial drug resistance. We have previously developed a whole-animal dual-screening platform that first used the nematode Caenorhabditis elegans, to identify low-toxicity antibacterial hits in a high-throughput format. The hits were then evaluated in the wax moth caterpillar Galleria mellonella infection model to confirm efficacy and low toxicity at a whole animal level. This multi-host approach is a powerful tool for revealing compounds that show antibacterial effects and relatively low toxicity at the whole organism level. This paper reports the use of the multi-host approach to identify and validate five new anti-staphylococcal compounds: (1) 4,4′,4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol(PPT), (2) (1S,2S)-2-[2-[[3-(1H-benzimidazol-2-yl)propyl]methylamino]ethyl]-6-fluoro-1,2,3,4-tetrahydro-1-(1-methylethyl)-2-naphthalenyl cyclopropanecarboxylate dihydrochloride(NNC), (3) 4,5,6,7-tetrabromobenzotriazole (TBB), (4) 3-[2-[2-chloro-4-[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methoxy]phenyl]ethenyl] benzoic acid(GW4064), and (5) N-(cyclopropylmethoxy)-3,4,5-trifluoro-2-[(4-iodo-2-methylphenyl)amino] benzamide(PD198306). The compounds reduced the severity of methicillin-resistant Staphylococcus aureus (MRSA, strain MW2) infections in both C. elegans and G. mellonella and showed minimal inhibitory concentrations (MICs) in the range of 2–8 µg/mL. Compounds NNC, PPT, and TBB permeabilized MRSA-MW2 cells to SYTOX green, suggesting that they target bacterial membranes. Compound TBB showed synergistic activity with doxycycline and oxacillin against MRSA-MW2, and compounds PPT, NNC, GW4064, and PD198306 synergized with doxycycline, polymyxin-B, gentamicin, and erythromycin, respectively. The study demonstrates the utility of the multi-host approach with follow-up hit characterization for prioritizing anti-MRSA compounds for further evaluation.

中文翻译：

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使用一种全动物秀丽隐杆线虫/梅勒菌廊顺序筛选方法鉴定的五种新型抗MRSA化合物的表征。

迫切需要应对日益增长的抗菌药物耐药性挑战。我们之前已经开发了一种全动物双重筛选平台，该平台首先使用线虫秀丽隐杆线虫（Caenorhabditis elegans）来鉴定高通量形式的低毒性抗菌素。然后在蜡蛾毛虫Galleria mellonella感染模型中评估命中，以确认在整个动物水平上的功效和低毒性。这种多宿主方法是揭示化合物的强大工具，这些化合物在整个生物体水平上均显示出抗菌作用和相对较低的毒性。本文报道了使用多宿主方法鉴定和验证五种新的抗葡萄球菌化合物：（1）4,4'，4″-（4-丙基-[1 H ]-吡唑-1,3,5 -三基）三酚（PPT），（2）（1 S，2 S）-2- [2-[[3-（1 H-苯并咪唑-2-基）丙基]甲基氨基]乙基] -6-氟-1,2 ，3,4-四氢-1-（1-甲基乙基）-2-萘基环丙烷甲酸二盐酸盐（NNC），（3）4,5,6,7-四溴苯并三唑（TBB），（4）3- [2- [2 -氯-4- [3-（2,6-二氯苯基）-5-（1-甲基乙基）-4-异恶唑基]甲氧基]苯基]乙烯基]苯甲酸（GW4064）和（5）N-（环丙基甲氧基）- 3,4,5-三氟-2-[（4-碘-2-甲基苯基）氨基]苯甲酰胺（PD198306）。这些化合物降低了秀丽隐杆线虫和梅勒霉菌中耐甲氧西林金黄色葡萄球菌（MRSA，菌株MW2）感染的严重性并显示最小抑制浓度（MIC）在2–8 µg / mL范围内。化合物NNC，PPT和TBB使MRSA-MW2细胞透化为SYTOX绿色，表明它们靶向细菌膜。化合物TBB与强力霉素和奥沙西林对MRSA-MW2具有协同活性，化合物PPT，NNC，GW4064和PD198306与强力霉素，多粘菌素B，庆大霉素和红霉素分别具有协同作用。这项研究证明了多宿主方法和后续命中特征可用于确定抗MRSA化合物的优先级，以进行进一步评估。