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Fast Biofilm Penetration and Anti-PAO1 Activity of Nebulized Azithromycin in Nanoarchaeosomes
journal contribution
posted on 2019-12-03, 15:23 authored by Maria
Julia Altube, Melina M. B. Martínez, Barbara Malheiros, Paulo C. Maffía, Leandro R. S. Barbosa, Maria Jose Morilla, Eder Lilia RomeroAzithromycin (AZ) is a broad-spectrum antibiotic with
anti-inflammatory
and antiquorum sensing activity against biofilm forming bacteria such
as Pseudomonas aeruginosa. AZ administered
by oral or parenteral routes, however, neither efficiently accesses
nor remains in therapeutic doses inside pulmonary biofilm depths.
Instead, inhaled nanocarriers loaded with AZ may revert the problem
of low accessibility and permanence of AZ into biofilms, enhancing
its antimicrobial activity. The first inhalable nanovesicle formulation
of AZ, nanoarchaeosome-AZ (nanoARC-AZ), is here presented. NanoARC
prepared with total polar archaeolipids (TPAs), rich in 2,3-di-O-phytanyl-sn-glycero-1-phospho-(3′-sn-glycerol-1′-methylphosphate) (PGP-Me) from Halorubrum tebenquichense archaebacteria, consisted
of ∼180 nm-diameter nanovesicles, loaded with 0.28 w/w AZ/TPA.
NanoARC-AZ displayed lower minimal inhibitory concentration and minimal
bactericidal concentration, higher preformed biofilm disruptive, and
anti-PAO1 activity in biofilms than AZ. NanoARC penetrated and disrupted
the structure of the PAO1 biofilm within only 1 h. Two milliliters
of 15 μg/mL AZ nanoARC-AZ nebulized for 5 min rendered AZ doses
compatible with in vitro antibacterial activity. The strong association
between AZ and the nanoARC bilayer, combined with electrostatic attraction
and trapping into perpendicular methyl groups of archaeolipids, as
determined by Laurdan fluorescence anisotropy, generalized polarization,
and small-angle X-ray scattering, was critical to stabilize during
storage and endure shear forces of nebulization. NanoARC-AZ was noncytotoxic
on A549 cells and human THP-1-derived macrophages, deserving further
preclinical exploration as enhancers of AZ anti-PAO1 activity.
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Keywords
biofilm depthsAZ anti-PAO 1 activityNebulized AzithromycinFast Biofilm PenetrationTPATHP -1-derived macrophagesnanoARC bilayerbactericidal concentrationAZ dosesanti-PAO 1 activityNanoarchaeosomes Azithromycinshear forcesinhalable nanovesicle formulationparenteral routesinhaled nanocarriersantimicrobial activityAnti-PAO 1 ActivityLaurdan fluorescence anisotropysmall-angle X-ray5 minmethyl groups549 cells1 hPAO 1 biofilmbroad-spectrum antibioticHalorubrum tebenquichense archaebacteriaPseudomonas aeruginosaglycero -1-phospho snpreformed biofilm
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