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(R)-Roscovitine and CFTR modulators enhance killing of multi-drug resistant Burkholderia cenocepacia by cystic fibrosis macrophages.
Shrestha, Chandra L; Zhang, Shuzhong; Wisniewski, Benjamin; Häfner, Stephanie; Elie, Jonathan; Meijer, Laurent; Kopp, Benjamin T.
Afiliação
  • Shrestha CL; Division of Pulmonary Medicine, Center for Microbial Pathogenesis, The Abigail Wexner Research Institute At Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH, 43205, USA.
  • Zhang S; Division of Pulmonary Medicine, Center for Microbial Pathogenesis, The Abigail Wexner Research Institute At Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH, 43205, USA.
  • Wisniewski B; Division of Pulmonary Medicine, Center for Microbial Pathogenesis, The Abigail Wexner Research Institute At Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH, 43205, USA.
  • Häfner S; Rudolf-Boehm-Institut F. Pharmakologie U. Toxikologie Medizinische Fakultät, Universität Leipzig, Leipzig, Germany.
  • Elie J; ManRos Therapeutics, Perharidy Peninsula, Roscoff, France.
  • Meijer L; ManRos Therapeutics, Perharidy Peninsula, Roscoff, France.
  • Kopp BT; Division of Pulmonary Medicine, Center for Microbial Pathogenesis, The Abigail Wexner Research Institute At Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH, 43205, USA. Benjamin.Kopp@NationwideChildrens.org.
Sci Rep ; 10(1): 21700, 2020 12 10.
Article em En | MEDLINE | ID: mdl-33303916
ABSTRACT
Cystic fibrosis (CF) is characterized by chronic bacterial infections and heightened inflammation. Widespread ineffective antibiotic use has led to increased isolation of drug resistant bacterial strains from respiratory samples. (R)-roscovitine (Seliciclib) is a unique drug that has many benefits in CF studies. We sought to determine roscovitine's impact on macrophage function and killing of multi-drug resistant bacteria. Human blood monocytes were isolated from CF (F508del/F508del) and non-CF persons and derived into macrophages (MDMs). MDMs were infected with CF clinical isolates of B. cenocepacia and P. aeruginosa. MDMs were treated with (R)-roscovitine or its main hepatic metabolite (M3). Macrophage responses to infection and subsequent treatment were determined. (R)-roscovitine and M3 significantly increased killing of B. cenocepacia and P. aeruginosa in CF MDMs in a dose-dependent manner. (R)-roscovitine-mediated effects were partially dependent on CFTR and the TRPC6 channel. (R)-roscovitine-mediated killing of B. cenocepacia was enhanced by combination with the CFTR modulator tezacaftor/ivacaftor and/or the alternative CFTR modulator cysteamine. (R)-roscovitine also increased MDM CFTR function compared to tezacaftor/ivacaftor treatment alone. (R)-roscovitine increases CF macrophage-mediated killing of antibiotic-resistant bacteria. (R)-roscovitine also enhances other macrophage functions including CFTR-mediated ion efflux. Effects of (R)-roscovitine are greatest when combined with CFTR modulators or cysteamine, justifying further clinical testing of (R)-roscovitine or optimized derivatives.
Assuntos

Texto completo: 1 Coleções: 01-internacional Temas: Geral Base de dados: MEDLINE Assunto principal: Fagocitose / Regulador de Condutância Transmembrana em Fibrose Cística / Fibrose Cística / Burkholderia cenocepacia / Roscovitina / Macrófagos Limite: Adolescent / Adult / Female / Humans / Male Idioma: En Revista: Sci Rep Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Temas: Geral Base de dados: MEDLINE Assunto principal: Fagocitose / Regulador de Condutância Transmembrana em Fibrose Cística / Fibrose Cística / Burkholderia cenocepacia / Roscovitina / Macrófagos Limite: Adolescent / Adult / Female / Humans / Male Idioma: En Revista: Sci Rep Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Estados Unidos