Multimetallic microparticles increase the potency of rifampicin against intracellular mycobacterium tuberculosis

Title: Multimetallic microparticles increase the potency of rifampicin against intracellular mycobacterium tuberculosis
Authors: Ellis, T
Chiappi, M
García-Trenco, A
Al-Ejji, M
Sarkar, S
Georgiou, TK
Shaffer, MSP
Tetley, TD
Schwander, S
Ryan, MP
Porter, AE
Item Type: Journal Article
Abstract: Mycobacterium tuberculosis ( M.tb) has the extraordinary ability to adapt to the administration of antibiotics through the development of resistance mechanisms. By rapidly exporting drugs from within the cytosol, these pathogenic bacteria diminish antibiotic potency and drive the presentation of drug-tolerant tuberculosis (TB). The membrane integrity of M.tb is pivotal in retaining these drug-resistant traits. Silver (Ag) and zinc oxide (ZnO) nanoparticles (NPs) are established antimicrobial agents that effectively compromise membrane stability, giving rise to increased bacterial permeability to antibiotics. In this work, biodegradable multimetallic microparticles (MMPs), containing Ag NPs and ZnO NPs, were developed for use in pulmonary delivery of antituberculous drugs to the endosomal system of M.tb-infected macrophages. Efficient uptake of MMPs by M.tb-infected THP1 cells was demonstrated using an in vitro macrophage infection model, with direct interaction between MMPs and M.tb visualized with the use of electron FIB-SEM tomography. The release of Ag NPs and ZnO NPs within the macrophage endosomal system increased the potency of the model antibiotic rifampicin by as much as 76%, realized through an increase in membrane disorder of intracellular M.tb. MMPs were effective at independently driving membrane destruction of extracellular bacilli located at the exterior face of THP1 macrophages. This MMP system presents as an effective drug delivery vehicle that could be used for the transport of antituberculous drugs such as rifampicin to infected alveolar macrophages, while increasing drug potency. By increasing M.tb membrane permeability, such a system may prove effectual in improving treatment of drug-susceptible TB in addition to M.tb strains considered drug-resistant.
Issue Date: 26-Jun-2018
Date of Acceptance: 16-May-2018
URI: http://hdl.handle.net/10044/1/60100
DOI: https://doi.org/10.1021/acsnano.7b08264
ISSN: 1936-0851
Publisher: American Chemical Society
Start Page: 5228
End Page: 5240
Journal / Book Title: ACS Nano
Volume: 12
Issue: 6
Copyright Statement: © 2018 American Chemical Society. This document is the Accepted Manuscript version of a Published Work that appeared in final form in [ACS Nano], after peer review and technical editing by the publisher. To access the final edited and published work see https://dx.doi.org/10.1021/acsnano.7b08264.
Sponsor/Funder: Royal Academy Of Engineering
Engineering & Physical Science Research Council (EPSRC)
Funder's Grant Number: MMRE_P56611
EP/K035274/1
Keywords: Science & Technology
Physical Sciences
Technology
Chemistry, Multidisciplinary
Chemistry, Physical
Nanoscience & Nanotechnology
Materials Science, Multidisciplinary
Chemistry
Science & Technology - Other Topics
Materials Science
tuberculosis
antibiotic resistance
drug delivery
Ag nanoparticle
ZnO nanoparticle
polymer
EFFLUX PUMP
VERAPAMIL ANALOGS
ESCHERICHIA-COLI
EPITHELIAL-CELLS
OUTER-MEMBRANE
NANOPARTICLES
SILVER
MACROPHAGES
ZINC
TOXICITY
Ag nanoparticle
ZnO nanoparticle
antibiotic resistance
drug delivery
polymer
tuberculosis
Ag nanoparticle
ZnO nanoparticle
antibiotic resistance
drug delivery
polymer
tuberculosis
Nanoscience & Nanotechnology
MD Multidisciplinary
Publication Status: Published
Conference Place: United States
Online Publication Date: 2018-05-16
Appears in Collections:Faculty of Engineering
Materials
Chemistry
National Heart and Lung Institute
Airway Disease
Faculty of Medicine
Faculty of Natural Sciences



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