Center for Microbial Pathogenesis, The Research Institute at Nationwide Children's Hospital, Columbus, OH, United States.
Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, United States.
J Cyst Fibros. 2019 Sep;18(5):622-629. doi: 10.1016/j.jcf.2018.10.010. Epub 2018 Oct 23.
There are no effective treatments for Burkholderia cenocepacia in patients with cystic fibrosis (CF) due to bacterial multi-drug resistance and defective host killing. We demonstrated that decreased bacterial killing in CF is caused by reduced macrophage autophagy due to defective cystic fibrosis transmembrane conductance regulator (CFTR) function. AR-12 is a small molecule autophagy inducer that kills intracellular pathogens such as Francisella. We evaluated the efficacy of AR-12 and a new analogue AR-13 in reducing bacterial burden in CF phagocytes.
Human CF and non-CF peripheral blood monocyte-derived macrophages, neutrophils, and nasal epithelial cells were exposed to CF bacterial strains in conjunction with treatment with antibiotics and/or AR compounds.
AR-13 and not AR-12 had growth inhibition on B. cenocepacia and methicillin-resistantStaphylococcus aureus (MRSA) in media alone. There was a 99% reduction in MRSA in CF macrophages, 71% reduction in Pseudomonas aeruginosa in CF neutrophils, and 70% reduction in non-CF neutrophils using AR-13. Conversely, there was no reduction in B. cenocepacia in infected CF and non-CF macrophages using AR-13 alone, but AR-13 and antibiotics synergistically reduced B. cenocepacia in CF macrophages. AR-13 improved autophagy in CF macrophages and CF patient-derived epithelial cells, and increased CFTR protein expression and channel function in CF epithelial cells.
The novel AR-12 analogue AR-13, in combination with antibiotics, reduced antibiotic-resistant bacterial burden in CF phagocytes, which correlated with increased autophagy and CFTR expression. AR-13 is a novel therapeutic for patients infected with B. cenocepacia and other resistant organisms that lack effective therapies.
由于细菌的多药耐药性和宿主杀伤功能缺陷，囊性纤维化（CF）患者的伯克霍尔德菌属无有效治疗方法。我们证明，由于囊性纤维化跨膜电导调节因子（CFTR）功能缺陷导致巨噬细胞自噬减少，CF 中的细菌杀伤能力降低。AR-12 是一种小分子自噬诱导剂，可杀死弗朗西斯菌等细胞内病原体。我们评估了 AR-12 和一种新类似物 AR-13 在减少 CF 吞噬细胞中细菌负荷的疗效。
将人类 CF 和非 CF 外周血单核细胞衍生的巨噬细胞、中性粒细胞和鼻上皮细胞暴露于 CF 细菌株中，并与抗生素和/或 AR 化合物联合治疗。
AR-13 而不是 AR-12 可单独在培养基中抑制伯克霍尔德菌属和耐甲氧西林金黄色葡萄球菌（MRSA）的生长。在 CF 巨噬细胞中，MRSA 减少了 99%，在 CF 中性粒细胞中，铜绿假单胞菌减少了 71%，在非 CF 中性粒细胞中减少了 70%，使用 AR-13。相反，单独使用 AR-13 并不能减少 CF 和非 CF 巨噬细胞中的伯克霍尔德菌属，但 AR-13 和抗生素协同减少 CF 巨噬细胞中的伯克霍尔德菌属。AR-13 改善了 CF 巨噬细胞和 CF 患者来源的上皮细胞中的自噬，并增加了 CF 上皮细胞中的 CFTR 蛋白表达和通道功能。
新型 AR-12 类似物 AR-13 与抗生素联合使用可降低 CF 吞噬细胞中抗生素耐药菌的负荷，这与自噬和 CFTR 表达的增加有关。AR-13 是一种新型治疗药物，适用于感染伯克霍尔德菌属和其他缺乏有效治疗方法的耐药病原体的患者。
