000084744 001__ 84744 000084744 005__ 20220309092436.0 000084744 0247_ $$2doi$$a10.1371/journal.pone.0220684 000084744 0248_ $$2sideral$$a114090 000084744 037__ $$aART-2019-114090 000084744 041__ $$aeng 000084744 100__ $$aHibbitts, Alan 000084744 245__ $$aCo-delivery of free vancomycin and transcription factor decoy-nanostructured lipid carriers can enhance inhibition of methicillin resistant Staphylococcus aureus (MRSA) 000084744 260__ $$c2019 000084744 5060_ $$aAccess copy available to the general public$$fUnrestricted 000084744 5203_ $$aBacterial 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. 000084744 536__ $$9info:eu-repo/grantAgreement/ES/MINECO/FPI-BES-2015-071304$$9info:eu-repo/grantAgreement/ES/MINECO/BIO2017-84246-C2-1-R$$9info:eu-repo/grantAgreement/ES/MICINN/SAF2017-84839-C2-2-R$$9info:eu-repo/grantAgreement/EC/FP7/604237/EU/Nanotherapeutics for antibiotic resistant emerging bacterial pathogens/NAREB$$9info:eu-repo/grantAgreement/ES/DGA/B35-17R 000084744 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttp://creativecommons.org/licenses/by/3.0/es/ 000084744 590__ $$a2.74$$b2019 000084744 591__ $$aMULTIDISCIPLINARY SCIENCES$$b27 / 71 = 0.38$$c2019$$dQ2$$eT2 000084744 592__ $$a1.023$$b2019 000084744 593__ $$aMultidisciplinary$$c2019$$dQ1 000084744 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion 000084744 700__ $$0(orcid)0000-0002-0111-4697$$aLucía, Ainhoa$$uUniversidad de Zaragoza 000084744 700__ $$0(orcid)0000-0002-1349-616X$$aSerrano-Sevilla, Inés 000084744 700__ $$0(orcid)0000-0001-6995-4302$$aDe Matteis, Laura 000084744 700__ $$aMcArthur, Michael 000084744 700__ $$0(orcid)0000-0003-1081-8482$$aDe La Fuente, Jesús M. 000084744 700__ $$0(orcid)0000-0003-2076-844X$$aAínsa, José A.$$uUniversidad de Zaragoza 000084744 700__ $$aNavarro, Fabrice 000084744 7102_ $$11008$$2630$$aUniversidad de Zaragoza$$bDpto. Microb.Med.Pr.,Sal.Públ.$$cÁrea Microbiología 000084744 773__ $$g14, 9 (2019), e0220684 [24 pp.]$$pPLoS One$$tPLoS ONE$$x1932-6203 000084744 8564_ $$s2281440$$uhttps://zaguan.unizar.es/record/84744/files/texto_completo.pdf$$yVersión publicada 000084744 8564_ $$s517013$$uhttps://zaguan.unizar.es/record/84744/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada 000084744 909CO $$ooai:zaguan.unizar.es:84744$$particulos$$pdriver 000084744 951__ $$a2022-03-09-09:17:43 000084744 980__ $$aARTICLE