Co-delivery of free vancomycin and transcription factor decoy-nanostructured lipid carriers can enhance inhibition of methicillin resistant Staphylococcus aureus (MRSA)

Hibbitts, Alan ; Lucía, Ainhoa (Universidad de Zaragoza) ; Serrano-Sevilla, Inés ; De Matteis, Laura ; McArthur, Michael ; De La Fuente, Jesús M. ; Aínsa, José A. (Universidad de Zaragoza) ; Navarro, Fabrice

Resumen: Bacterial resistance to antibiotics is widely regarded as a major public health concern with last resort MRSA treatments like vancomycin now encountering resistant strains. TFDs (Transcription Factor Decoys) are oligonucleotide copies of the DNA-binding sites for transcription factors. They bind to and sequester the targeted transcription factor, thus inhibiting transcription of many genes. By developing TFDs with sequences aimed at inhibiting transcription factors controlling the expression of highly conserved bacterial cell wall proteins, TFDs present as a potential method for inhibiting microbial growth without encountering typical resistance mechanisms. However, the efficient protection and delivery of the TFDs inside the bacterial cells is a critical step for the success of this technology. Therefore, in our study, specific TFDs against S. aureus were complexed with two different types of nanocarriers: cationic nanostructured lipid carriers (cNLCs) and chitosan-based nanoparticles (CSNCs). These TFD-carrier nanocomplexes were characterized for size, zeta potential and TFD complexation or loading efficiency in a variety of buffers. In vitro activity of the nanocomplexes was examined alone and in combination with vancomycin, first in methicillin susceptible strains of S. aureus with the lead candidate advancing to tests against MRSA cultures. Results found that both cNLCs and chitosan-based carriers were adept at complexing and protecting TFDs in a range of physiological and microbiological buffers up to 72 hours. From initial testing, chitosan-TFD particles demonstrated no visible improvements in effect when co-administered with vancomycin. However, co-delivery of cNLC-TFD with vancomycin reduced the MIC of vancomycin by over 50% in MSSA and resulted in significant decreases in viability compared with vancomycin alone in MRSA cultures. Furthermore, these TFD-loaded particles demonstrated very low levels of cytotoxicity and haemolysis in vitro. To our knowledge, this is the first attempt at a combined antibiotic/oligonucleotide-TFD approach to combatting MRSA and, as such, highlights a new avenue of MRSA treatment combining traditional small molecules drugs and bacterial gene inhibition. © 2019 Hibbitts et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Idioma: Inglés

DOI: 10.1371/journal.pone.0220684

Año: 2019

Publicado en: PLoS ONE 14, 9 (2019), e0220684 [24 pp.]
ISSN: 1932-6203

Factor impacto JCR: 2.74 (2019)

Categ. JCR: MULTIDISCIPLINARY SCIENCES rank: 27 / 71 = 0.38 (2019) - Q2 - T2

Factor impacto SCIMAGO: 1.023 - Multidisciplinary (Q1)

Financiación: info:eu-repo/grantAgreement/ES/DGA/B35-17R
Financiación: info:eu-repo/grantAgreement/EC/FP7/604237/EU/Nanotherapeutics for antibiotic resistant emerging bacterial pathogens/NAREB
Financiación: info:eu-repo/grantAgreement/ES/MICINN/SAF2017-84839-C2-2-R
Financiación: info:eu-repo/grantAgreement/ES/MINECO/BIO2017-84246-C2-1-R
Financiación: info:eu-repo/grantAgreement/ES/MINECO/FPI-BES-2015-071304

Tipo y forma: Artículo (Versión definitiva)

Área (Departamento): Área Microbiología (Dpto. Microb.Med.Pr.,Sal.Públ.)