Su Ma, Xia Donglin, Teng Peng, Nimmagadda Alekhya, Zhang Chao, Odom Timothy, Cao Annie, Hu Yong, Cai Jianfeng
Department of Chemistry, University of South Florida , 4202 E. Fowler Ave, Tampa, Florida 33620, United States.
Department of Biomedical Engineering, College of Engineering and Applied Science, Nanjing University , 22 Hankou Road, Nanjing, Jiangsu 210093, P. R. China.
J Med Chem. 2017 Oct 26;60(20):8456-8465. doi: 10.1021/acs.jmedchem.7b00847. Epub 2017 Oct 6.
Hydantoin (imidazolidinedione) derivatives such as nitrofurantoin are small molecules that have aroused considerable interest recently due to their low rate of bacterial resistance. However, their moderate antimicrobial activity may hamper their application combating antibiotic resistance in the long run. Herein, we report the design of bacterial membrane-active hydantoin derivatives, from which we identified compounds that show much more potent antimicrobial activity than nitrofurantoin against a panel of clinically relevant Gram-positive and Gram-negative bacterial strains. These compounds are able to act on bacterial membranes, analogous to natural host-defense peptides. Additionally, these hydantoin compounds not only kill bacterial pathogens rapidly but also prevent the development of methicillin-resistant Staphylococcus aureus (MRSA) bacterial resistance under the tested conditions. More intriguingly, the lead compound exhibited in vivo efficacy that is much superior to vancomycin by eradicating bacteria and suppressing inflammation caused by MRSA-induced pneumonia in a rat model, demonstrating its promising therapeutic potential.
乙内酰脲（咪唑烷二酮）衍生物，如呋喃妥因，是小分子化合物，由于其低细菌耐药率，最近引起了相当大的关注。然而，它们中等的抗菌活性可能会从长远上阻碍其在对抗抗生素耐药性方面的应用。在此，我们报告了具有细菌膜活性的乙内酰脲衍生物的设计，从中我们鉴定出了一些化合物，这些化合物对一系列临床相关的革兰氏阳性和革兰氏阴性细菌菌株显示出比呋喃妥因更强的抗菌活性。这些化合物能够作用于细菌膜，类似于天然宿主防御肽。此外，这些乙内酰脲化合物不仅能迅速杀死细菌病原体，还能在测试条件下防止耐甲氧西林金黄色葡萄球菌（MRSA）产生耐药性。更有趣的是，先导化合物在大鼠模型中通过根除细菌和抑制MRSA诱导的肺炎引起的炎症，表现出比万古霉素优越得多的体内疗效，证明了其有前景的治疗潜力。
