AR-13 reduces antibiotic-resistant bacterial burden in cystic fibrosis phagocytes and improves cystic fibrosis transmembrane conductance regulator function.

Autor: Assani K; Center for Microbial Pathogenesis, The Research Institute at Nationwide Children's Hospital, Columbus, OH, United States., Shrestha CL; Center for Microbial Pathogenesis, The Research Institute at Nationwide Children's Hospital, Columbus, OH, United States., Rinehardt H; Center for Microbial Pathogenesis, The Research Institute at Nationwide Children's Hospital, Columbus, OH, United States., Zhang S; Center for Microbial Pathogenesis, The Research Institute at Nationwide Children's Hospital, Columbus, OH, United States., Robledo-Avila F; Center for Microbial Pathogenesis, The Research Institute at Nationwide Children's Hospital, Columbus, OH, United States., Wellmerling J; Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, United States., Partida-Sanchez S; Center for Microbial Pathogenesis, The Research Institute at Nationwide Children's Hospital, Columbus, OH, United States., Cormet-Boyaka E; Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, United States., Reynolds SD; Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH, United States., Schlesinger LS; Texas Biomedical Research Institute, San Antonio, TX, United States., Kopp BT; Center for Microbial Pathogenesis, The Research Institute at Nationwide Children's Hospital, Columbus, OH, United States; Division of Pulmonary Medicine, Nationwide Children's Hospital, Columbus, OH, United States. Electronic address: Benjamin.Kopp@NationwideChildrens.org.
Jazyk: angličtina
Zdroj: Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society [J Cyst Fibros] 2019 Sep; Vol. 18 (5), pp. 622-629. Date of Electronic Publication: 2018 Oct 23.
DOI: 10.1016/j.jcf.2018.10.010
Abstrakt: Background: 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.
Methods: 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.
Results: 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.
Conclusions: 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.
(Copyright © 2018 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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