(E, E)-farnesol and myristic acid-loaded lipid nanoparticles overcome colistin resistance in Acinetobacter baumannii
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| Titel: | (E, E)-farnesol and myristic acid-loaded lipid nanoparticles overcome colistin resistance in Acinetobacter baumannii |
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| Autoren: | Faivre, Carla, Imtiyaz, Farras Daffa, Buyck, Julien, Marchand, Sandrine, Marcotte, Melissa, Henry, Thomas, Anton, Nicolas, Collot, Mayeul, Tewes, Frédéric |
| Weitere Verfasser: | Laboratoire de Bioimagerie et Pathologies (LBP), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Nanomédecine Régénérative (NanoRegMed), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Pharmacologie des anti-infectieux et antibiorésistance U 1070 (PHAR2 Poitiers ), Université de Poitiers = University of Poitiers (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier universitaire de Poitiers = Poitiers University Hospital (CHU de Poitiers La Milétrie ), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon), Université de Lyon-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Inflammasome, Infections bactériennes et autoinflammation, Inflammasome, Bacterial Infections and Autoinflammation CIRI (CIRI-I2BA), Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon), ANR-21-CE18-0054,PAANIC,Administration pulmonaire de nano-émulsion antibiotique pour le traitement d'infections à bactéries gram-négatives(2021) |
| Quelle: | ISSN: 0378-5173 ; International Journal of Pharmaceutics ; https://hal.science/hal-04766832 ; International Journal of Pharmaceutics, 2024, 667 (A), pp.124907. ⟨10.1016/j.ijpharm.2024.124907⟩ ; https://www.sciencedirect.com/science/article/pii/S0378517324011414. |
| Verlagsinformationen: | CCSD Elsevier |
| Publikationsjahr: | 2024 |
| Schlagwörter: | Galleria mellonella, Colistin, Antibiotic adjuvant, Bacterial infections, Acinetobacter baumannii, Lipid nanoparticles, MESH: Acinetobacter baumannii* / drug effects, MESH: Animals, MESH: Anti-Bacterial Agents* / administration & dosage, MESH: Anti-Bacterial Agents* / chemistry, MESH: Anti-Bacterial Agents* / pharmacology, MESH: Colistin* / administration & dosage, MESH: Colistin* / pharmacology, MESH: Drug Resistance, Bacterial* / drug effects, MESH: Farnesol* / administration & dosage, MESH: Farnesol* / chemistry, MESH: Farnesol* / pharmacology, MESH: Larva / drug effects, MESH: Lipids / chemistry, MESH: Liposomes, MESH: Microbial Sensitivity Tests, MESH: Moths, MESH: Myristic Acid* / chemistry, MESH: Nanoparticles* / chemistry, [CHIM]Chemical Sciences, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology |
| Beschreibung: | International audience ; The rise of colistin-resistant Acinetobacter baumannii has severely limited treatment options for infections caused by this pathogen. While terpene alcohols and fatty acids have shown potential to enhance colistin’s efficacy, but their high lipophilicity limits their clinical application. To address this, we developed water-dispersible lipid nanoparticles (LNPs) in two sizes (40 nm and 130 nm), loaded with these compounds to act as colistin adjuvants. Among eleven LNP formulations, six significantly reduced colistin’s minimum inhibitory concentration (MIC) by 16- to 64-fold. The most effective, featuring (E,E)-farnesol and myristic acid, were further examined for bactericidal activity, membrane disruption, cytotoxicity, and in vivo efficacy in Galleria mellonella larvae. Time-kill studies demonstrated that at an adjuvant concentration of 60 mg/L, these LNPs eradicated bacteria when combined with 4 mg/L free colistin for resistant isolates (MIC = 128 mg/L) and 0.06 mg/L for susceptible isolates (MIC = 0.5 mg/L), without regrowth. Myristic acid-loaded LNPs combined with free colistin at 1/8 MIC resulted in a 4.2-fold higher mortality rate than the combination with (E,E)-farnesol-loaded LNPs in resistant strains. This result was correlated with a 45-fold faster increase in inner membrane permeability, measured by propidium iodide (PI) uptake, in the presence of myristic acid-loaded LNPs compared with a 13-fold faster increase with (E,E)-farnesol-loaded LNPs. DiSC3(5) assays revealed that LNPs alone depolarised the bacterial inner membrane, with enhanced effects when combined with colistin at 1/8 MIC, a result not observed with colistin alone at this concentration. As with PI uptake, this inner membrane depolarising effect was more pronounced with myristic acid-loaded LNPs than with (E,E)-farnesol-loaded LNPs in resistant strains, suggesting that the colistin adjuvant effect of these lipophilic compounds is due to their ability to help colistin destabilise the bacterial inner membrane. ... |
| Publikationsart: | article in journal/newspaper |
| Sprache: | English |
| Relation: | info:eu-repo/semantics/altIdentifier/pmid/39500471; PUBMED: 39500471 |
| DOI: | 10.1016/j.ijpharm.2024.124907 |
| Verfügbarkeit: | https://hal.science/hal-04766832 https://hal.science/hal-04766832v1/document https://hal.science/hal-04766832v1/file/%28E%20_%20E%29-farnesol%20and%20myristic%20acid-loaded%20lipid%20nanoparticles%20overcome.pdf https://doi.org/10.1016/j.ijpharm.2024.124907 |
| Rights: | http://creativecommons.org/licenses/by/ ; info:eu-repo/semantics/OpenAccess |
| Dokumentencode: | edsbas.FA3BCF91 |
| Datenbank: | BASE |
Nájsť tento článok vo Web of Science | Abstract: | International audience ; The rise of colistin-resistant Acinetobacter baumannii has severely limited treatment options for infections caused by this pathogen. While terpene alcohols and fatty acids have shown potential to enhance colistin’s efficacy, but their high lipophilicity limits their clinical application. To address this, we developed water-dispersible lipid nanoparticles (LNPs) in two sizes (40 nm and 130 nm), loaded with these compounds to act as colistin adjuvants. Among eleven LNP formulations, six significantly reduced colistin’s minimum inhibitory concentration (MIC) by 16- to 64-fold. The most effective, featuring (E,E)-farnesol and myristic acid, were further examined for bactericidal activity, membrane disruption, cytotoxicity, and in vivo efficacy in Galleria mellonella larvae. Time-kill studies demonstrated that at an adjuvant concentration of 60 mg/L, these LNPs eradicated bacteria when combined with 4 mg/L free colistin for resistant isolates (MIC = 128 mg/L) and 0.06 mg/L for susceptible isolates (MIC = 0.5 mg/L), without regrowth. Myristic acid-loaded LNPs combined with free colistin at 1/8 MIC resulted in a 4.2-fold higher mortality rate than the combination with (E,E)-farnesol-loaded LNPs in resistant strains. This result was correlated with a 45-fold faster increase in inner membrane permeability, measured by propidium iodide (PI) uptake, in the presence of myristic acid-loaded LNPs compared with a 13-fold faster increase with (E,E)-farnesol-loaded LNPs. DiSC3(5) assays revealed that LNPs alone depolarised the bacterial inner membrane, with enhanced effects when combined with colistin at 1/8 MIC, a result not observed with colistin alone at this concentration. As with PI uptake, this inner membrane depolarising effect was more pronounced with myristic acid-loaded LNPs than with (E,E)-farnesol-loaded LNPs in resistant strains, suggesting that the colistin adjuvant effect of these lipophilic compounds is due to their ability to help colistin destabilise the bacterial inner membrane. ... |
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| DOI: | 10.1016/j.ijpharm.2024.124907 |