The Lundquist Institute for Biomedical Innovations at Harbor-University of California Los Angeles (UCLA) Medical Center, Torrance, California, USA.
College of Wildlife Resources, Northeast Forestry University, Harbin, China.
Antimicrob Agents Chemother. 2020 Jul 22;64(8). doi: 10.1128/AAC.00303-20.
The rise in multidrug-resistant (MDR) organisms portends a serious global threat to the health care system with nearly untreatable infectious diseases, including pneumonia and its often fatal sequelae, acute respiratory distress syndrome (ARDS) and sepsis. Gram-negative bacteria (GNB), including , , and carbapenemase-producing (CPKP), are among the World Health Organization's and National Institutes of Health's high-priority MDR pathogens for targeted development of new therapies. Here, we show that stabilizing the host's vasculature by genetic deletion or pharmacological inhibition of the small GTPase ADP-ribosylation factor 6 (ARF6) increases survival rates of mice infected with , , and CPKP. We show that the pharmacological inhibition of ARF6-GTP phenocopies endothelium-specific disruption in enhancing the survival of mice with pneumonia, suggesting that inhibition is on target. Finally, we show that the mechanism of protection elicited by these small-molecule inhibitors acts by the restoration of vascular integrity disrupted by GNB lipopolysaccharide (LPS) activation of the TLR4/MyD88/ARNO/ARF6 pathway. By targeting the host's vasculature with small-molecule inhibitors of ARF6 activation, we circumvent microbial drug resistance and provide a potential alternative/adjunctive treatment for emerging and reemerging pathogens.
多重耐药（MDR）生物体的增加预示着全球医疗保健系统面临着严重的威胁，因为几乎无法治疗的传染病，包括肺炎及其常致命的后果，急性呼吸窘迫综合征（ARDS）和败血症。革兰氏阴性菌（GNB），包括 、 和产碳青霉烯酶的 （CPKP），是世界卫生组织和美国国立卫生研究院针对新疗法的靶向开发的高优先级 MDR 病原体之一。在这里，我们通过遗传敲除或药理学抑制小 GTPase ADP-ribosylation factor 6（ARF6）来稳定宿主的脉管系统，发现这增加了感染 、 和 CPKP 的小鼠的存活率。我们发现 ARF6-GTP 的药理学抑制可模拟内皮细胞特异性 破坏，从而提高肺炎小鼠的存活率，这表明抑制是有针对性的。最后，我们发现这些小分子抑制剂所引起的保护机制是通过恢复由 GNB 脂多糖（LPS）激活 TLR4/MyD88/ARNO/ARF6 通路破坏的血管完整性来实现的。通过用 ARF6 激活的小分子抑制剂靶向宿主的脉管系统，我们规避了微生物的耐药性，并为新兴和再现的病原体提供了一种潜在的替代/辅助治疗方法。
