Multidrug-resistant pathogens pose a serious threat to human health. For decades, the antibiotic vancomycin has been a potent option when treating Gram-positive multidrug-resistant infections. Nonetheless, in recent decades, we have begun to see an increase in vancomycin-resistant bacteria. Here, we show that the nuclear factor-kappa B (NF-κB) inhibitor N-[3,5-Bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide (IMD0354) was identified as a positive hit through a Caenorhabditis elegans–methicillin-resistant Staphylococcus aureus (MRSA) infection screen. IMD0354 was a potent bacteriostatic drug capable of working at a minimal inhibitory concentration (MIC) as low as 0.06 µg/mL against various vancomycin-resistant strains. Interestingly, IMD0354 showed no hemolytic activity at concentrations as high as 16 µg/mL and is minimally toxic to C. elegans in vivo with 90% survival up to 64 µg/mL. In addition, we demonstrated that IMD0354′s mechanism of action at high concentrations is membrane permeabilization. Lastly, we found that IMD0354 is able to inhibit vancomycin-resistant Staphylococcus aureus (VRSA) initial cell attachment and biofilm formation at sub-MIC levels and above. Our work highlights that the NF-κB inhibitor IMD0354 has promising potential as a lead compound and an antimicrobial therapeutic candidate capable of combating multidrug-resistant bacteria.

中文翻译：

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对激酶抑制剂IMD0354的多药耐药革兰氏阳性细菌具有新的抗菌生物活性

耐多药病原体严重威胁人类健康。几十年来，抗生素万古霉素一直是治疗革兰氏阳性多药耐药性感染的有效选择。但是，在最近的几十年中，我们已经开始看到耐万古霉素的细菌有所增加。在这里，我们表明，核因子-κB（NF-κB）抑制剂N- [3,5-双（三氟甲基）苯基] -5-氯-2-羟基苯甲酰胺（IMD0354）被鉴定为通过秀丽隐杆线虫阳性线虫–耐甲氧西林金黄色葡萄球菌（MRSA）感染屏幕。IMD0354是一种有效的抑菌药物，对各种耐万古霉素的菌株的最小抑菌浓度（MIC）低至0.06 µg / mL。有趣的是，IMD0354在高达16 µg / mL的浓度下没有显示溶血活性，并且对秀丽隐杆线虫的体内毒性最小，在高达64 µg / mL的条件下存活率为90％。此外，我们证明了IMD0354在高浓度下的作用机理是膜通透性。最后，我们发现IMD0354能够抑制耐万古霉素的金黄色葡萄球菌（VRSA）低于MIC水平及以上的初始细胞附着和生物膜形成。我们的工作强调，NF-κB抑制剂IMD0354具有潜在的潜力，可以作为先导化合物和能够对抗多药耐药细菌的抗菌药物候选者。