Escobar Iliana E, White Alexis, Kim Wooseong, Mylonakis Eleftherios
Infectious Diseases Division, Department of Medicine, Warren Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI 02903, USA.
College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Korea.
Antibiotics (Basel). 2020 Oct 1;9(10):665. doi: 10.3390/antibiotics9100665.
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 -[3,5-Bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide (IMD0354) was identified as a positive hit through a -methicillin-resistant (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 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 (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.
多重耐药病原体对人类健康构成严重威胁。几十年来，抗生素万古霉素一直是治疗革兰氏阳性多重耐药感染的有效选择。然而，近几十年来，我们开始看到耐万古霉素细菌数量有所增加。在此，我们表明核因子-κB（NF-κB）抑制剂-[3,5-双（三氟甲基）苯基]-5-氯-2-羟基苯甲酰胺（IMD0354）通过耐甲氧西林金黄色葡萄球菌（MRSA）感染筛选被确定为阳性结果。IMD0354是一种强效抑菌药物，对各种耐万古霉素菌株的最低抑菌浓度（MIC）低至0.06μg/mL。有趣的是，IMD0354在高达16μg/mL的浓度下无溶血活性，在体内毒性极小，在高达64μg/mL时存活率达90%。此外，我们证明了IMD0354在高浓度下的作用机制是膜通透化。最后，我们发现IMD0354能够在亚MIC水平及以上抑制耐万古霉素金黄色葡萄球菌（VRSA）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作为一种先导化合物和能够对抗多重耐药细菌的抗菌治疗候选药物具有广阔的潜力。
