Multimetallic Microparticles Increase the Potency of Rifampicin against Intracellular Mycobacterium tuberculosis

Timothy Ellis, Michele Chiappi, Andrés García-Trenco, Maryam Al-Ejji, Srijata Sarkar, Theoni K. Georgiou, Milo S.P. Shaffer, Teresa D. Tetley, Stephan Schwander, Mary P. Ryan, Alexandra E. Porter

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)5228-5240
Number of pages13
JournalACS Nano
Volume12
Issue number6
DOIs
StatePublished - Jun 26 2018

Fingerprint

tuberculosis
microparticles
Rifampin
Macrophages
Antibiotics
drugs
Nanoparticles
Membranes
Zinc oxide
macrophages
Zinc Oxide
Pharmaceutical Preparations
antibiotics
Anti-Bacterial Agents
membranes
nanoparticles
zinc oxides
Antimicrobial agents
Bacilli
Drug delivery

All Science Journal Classification (ASJC) codes

  • Materials Science(all)
  • Engineering(all)
  • Physics and Astronomy(all)

Keywords

  • Ag nanoparticle
  • ZnO nanoparticle
  • antibiotic resistance
  • drug delivery
  • polymer
  • tuberculosis

Cite this

Ellis, T., Chiappi, M., García-Trenco, A., Al-Ejji, M., Sarkar, S., Georgiou, T. K., ... Porter, A. E. (2018). Multimetallic Microparticles Increase the Potency of Rifampicin against Intracellular Mycobacterium tuberculosis. ACS Nano, 12(6), 5228-5240. https://doi.org/10.1021/acsnano.7b08264
Ellis, Timothy ; Chiappi, Michele ; García-Trenco, Andrés ; Al-Ejji, Maryam ; Sarkar, Srijata ; Georgiou, Theoni K. ; Shaffer, Milo S.P. ; Tetley, Teresa D. ; Schwander, Stephan ; Ryan, Mary P. ; Porter, Alexandra E. / Multimetallic Microparticles Increase the Potency of Rifampicin against Intracellular Mycobacterium tuberculosis. In: ACS Nano. 2018 ; Vol. 12, No. 6. pp. 5228-5240.
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Ellis, T, Chiappi, M, García-Trenco, A, Al-Ejji, M, Sarkar, S, Georgiou, TK, Shaffer, MSP, Tetley, TD, Schwander, S, Ryan, MP & Porter, AE 2018, 'Multimetallic Microparticles Increase the Potency of Rifampicin against Intracellular Mycobacterium tuberculosis', ACS Nano, vol. 12, no. 6, pp. 5228-5240. https://doi.org/10.1021/acsnano.7b08264

Multimetallic Microparticles Increase the Potency of Rifampicin against Intracellular Mycobacterium tuberculosis. / Ellis, Timothy; Chiappi, Michele; García-Trenco, Andrés; Al-Ejji, Maryam; Sarkar, Srijata; Georgiou, Theoni K.; Shaffer, Milo S.P.; Tetley, Teresa D.; Schwander, Stephan; Ryan, Mary P.; Porter, Alexandra E.

In: ACS Nano, Vol. 12, No. 6, 26.06.2018, p. 5228-5240.

Research output: Contribution to journalArticle

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AU - Ellis, Timothy

AU - Chiappi, Michele

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AU - Al-Ejji, Maryam

AU - Sarkar, Srijata

AU - Georgiou, Theoni K.

AU - Shaffer, Milo S.P.

AU - Tetley, Teresa D.

AU - Schwander, Stephan

AU - Ryan, Mary P.

AU - Porter, Alexandra E.

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N2 - 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.

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Ellis T, Chiappi M, García-Trenco A, Al-Ejji M, Sarkar S, Georgiou TK et al. Multimetallic Microparticles Increase the Potency of Rifampicin against Intracellular Mycobacterium tuberculosis. ACS Nano. 2018 Jun 26;12(6):5228-5240. https://doi.org/10.1021/acsnano.7b08264