Testing a human antimicrobial RNase chimera against bacterial resistance
Prats-Ejarque, Guillem (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Li, Jiarui (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Ait-Ichou, Fatima (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Lorente, Helena (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Boix i Borràs, Esther (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)

Data:	2019
Resum:	The emergence of bacterial resistance to the most commonly used antibiotics encourages the design of novel antimicrobial drugs. Antimicrobial proteins and peptides (AMPs) are the key players in host innate immunity. They exert a rapid and multifaceted action that reduces the development of bacterial adaptation mechanisms. Human antimicrobial RNases belonging to the vertebrate specific RNase A superfamily participate in the maintenance of tissue and body fluid sterility. Among the eight human canonical RNases, RNase 3 stands out as the most cationic and effective bactericidal protein against Gram-negative species. Its enhanced ability to disrupt the bacterial cell wall has evolved in detriment of its catalytic activity. Based on structure-functional studies we have designed an RNase 3/1 hybrid construct that combines the high catalytic activity of RNase 1 with RNase 3 bactericidal properties. Next, we have explored the ability of this hybrid RNase to target the development of bacterial resistance on an Acinetobacter baumannii cell culture. Synergy assays were performed in combination with colistin, a standard antimicrobial peptide used as an antibiotic to treat severe infections. Positive synergism was observed between colistin and the RNase 3/1 hybrid protein. Subsequently, using an in vitro experimental evolution assay, by exposure of a bacterial culture to colistin at incremental doses, we demonstrated the ability of the RNase 3/1 construct to reduce the emergence of bacterial antimicrobial resistance. The results advance the potential applicability of RNase-based drugs as antibiotic adjuvants.
Ajuts:	Ministerio de Economía y Competitividad SAF2015-66007P Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/SGR-1010 Agència de Gestió d'Ajuts Universitaris i de Recerca 2016/PROD-00060
Nota:	Altres ajuts: This work was supported by Fundació La Marató de TV3 (Ref. 20180310)
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	RNase ; Antimicrobial resistance ; Antibiotic adjuvant ; Gram-negative bacteria ; Antimicrobial peptides
Publicat a:	Frontiers in microbiology, Vol. 10 (June 2019) , art. 1357, ISSN 1664-302X

DOI: 10.3389/fmicb.2019.01357
PMID: 31275278

14 p, 2.5 MB

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