Multimetallic Microparticles Increase the Potency of Rifampicin against Intracellular Mycobacterium tuberculosis

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.

Biocompatibility and photo-induced antibacterial activity of lignin-stabilized noble metal nanoparticles

“…Threats posed by bacterial infections are of major public concern, leading to a boost in efforts to develop new antimicrobial agents. 1 The use of silver nanoparticles (AgNP) has been widely explored, [2][3][4] showing antimicrobial activity in the dark and under illumination. 5,6 Whereas some studies suggest silver nanoparticles are a simple source of silver ions, 7 a few years back our group demonstrated that the mechanism is more complex 8 and may involve direct action by the nanoparticles themselves.…”

Consideration of Metal Organic Frameworks for Respiratory Delivery

“…However, there is evidence that a variety of transition metals can be advantageous in the treatment of pulmonary bacterial ailments. Ag, Cu, Fe, Pd, and Zn have been suggested for tuberculosis (TB) (Chao A. et al, 2019;Ellis T. et al, 2018;Palazzo F. et al, 2013;Pieters J., 2008;Poole K., 2017), Ag and Pt for lung cancer (with some evidence of dose-dependent toxicity) (Foldbjerg R. et al, 2011;Ndagi U. et al, 2017), and Ag, Cu, and Zn for viruses, including coronavirus (Bright K.R. et al, 2008;Raha S. et al, 2020;Ranford J.D.…”

<p>Silver Nanoparticles for the Therapy of Tuberculosis</p>

“…A similar effect of multimetallic nanoparticles (MMN) including AgNP for intramacrophagic mycobacteria was reported by Ellis etal. 218 Although internalized within the phagolysosomal apparatus, the AgNP have a limited antitubercular effect for the intracellular bacteria, but increase the antitubercular effect of rifampicin. The co-administration of rifampicin led to a reduction of 68% of M. tuberculosis colony-forming units.…”