Polyacrylic Acid-Coated Iron Oxide Nanoparticles for Targeting Drug Resistance in Mycobacteria

Abstract

The emergence of drug resistance is a major problem faced in current tuberculosis (TB) therapy, representing a global health concern. Mycobacterium is naturally resistant to most drugs due to export of the latter outside bacterial cells by active efflux pumps, resulting in a low intracellular drug concentration. Thus, development of agents that can enhance the effectiveness of drugs used in TB treatment and bypass the efflux mechanism is crucial. In this study, we present a new nanoparticle-based strategy for enhancing the efficacy of existing drugs. To that end, we have developed poly(acrylic acid) (PAA)-coated iron oxide (magnetite) nanoparticles (PAA-MNPs) as efflux inhibitors and used it together with rifampicin (a first line anti-TB drug) on Mycobacterium smegmatis. PAA-MNPs of mean diameter 9 nm interact with bacterial cells via surface attachment and are then internalized by cells. Although PAA-MNP alone does not inhibit cell growth, treatment of cells with a combination of PAA-MNP and rifampicin exhibits a synergistic 4-fold-higher growth inhibition compared to rifampicin alone. This is because the combination of PAA-MNP and rifampicin results in up to a 3-fold-increased accumulation of rifampicin inside the cells. This enhanced intracellular drug concentration has been explained by real-time transport studies on a common efflux pump substrate, ethidium bromide (EtBr). It is seen that PAA-MNP increases the accumulation of EtBr significantly and also minimizes the EtBr efflux in direct proportion to the PAA-MNP concentration. Our results thus illustrate that the addition of PAA-MNP with rifampicin may bypass the innate drug resistance mechanism of M. smegmatis. This generic strategy is also found to be successful for other anti-TB drugs, such as isoniazid and fluoroquinolones (e.g., norfloxacin), only when stabilized, coated nanoparticles (such as PAA-MNP) are used, not PAA or MNP alone. We hence establish coated nanoparticles as a new class of efflux inhibitors for potential therapeutic use.

Nanoparticles as Efflux Pump and Biofilm Inhibitor to Rejuvenate Bactericidal Effect of Conventional Antibiotics

“…One possible mechanism is the direct binding of metal nanoparticles to the active site of efflux pumps, blocking the extrusion of antibiotics outside the cells. Metal nanoparticles may here act as a competitive inhibitor of antibiotic for the binding site of efflux pumps [18]. Another possible mechanism is through the disruption of efflux kinetics.…”

“…The effect of silver nanoparticles for disruption of the efflux kinetics of MDR efflux pump, MexAM-OPrM, has already been examined in P. aeruginosa [19]. It may be suggested that metal nanoparticles may lead to termination of proton gradient followed by disruption of membrane potential or loss of proton motive force (PMF), resulting in deterioration of driving force essential for efflux pump activity [18, 20, 21]. However, the major constraint in the direct binding of nanoparticles with efflux pumps is their small size and reactivity.…”

Effect of Surface Charge and Hydrophobicity Modulation on the Antibacterial and Antibiofilm Potential of Magnetic Iron Nanoparticles

“…MNPs range in size from few to hundreds of nanometers [6]. They have many bioapplications, such as magnetic bioseparation and detection of biological entities, diagnostic applications as magnetic resonance imaging, and therapeutic applications as targeted drug delivery and biological labels [7].…”

“…Surface coating of 2 Journal of Nanomaterials [7] * The OA-IONPs showed more potent antibiofilm inhibitory activity against Gram-positive bacteria S. aureus as compared to Gram-negative bacteria P.…”

Magnetic hydroxyapatite: a promising multifunctional platform for nanomedicine application

“…15 Ma et al synthesized PAA-coated magnetite nanoparticles (PAA-MNPs, 246 nm) and studied magnetically targeted thrombolysis with recombinant tissue plasminogen activator bound to PAA-MNPs. 16 Denizot et al reported the synthesis of phosphorylcholine-coated iron oxide nanoparticles (5 nm) for use as MRI contrast agent.…”