Rifampicin-Loaded Polyelectrolyte Complex Eliminates Intracellular Bacteria through Thiol-Mediated Cellular Uptake...

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Infectious Diseases

Background:

• Intracellular bacteria pose a treatment challenge due to poor antibiotic accumulation in the cytoplasm.
• Effective strategies are needed to enhance antibiotic delivery and efficacy against intracellular pathogens.

Purpose of the Study:

• To develop a polyelectrolyte complex (PECs@Rif) for direct cytosolic delivery of rifampicin (Rif) to combat intracellular bacterial infections.
• To investigate the mechanism of enhanced bacterial eradication via thiol-mediated uptake and ROS generation.

Main Methods:

• Formation of a polyelectrolyte complex (PECs@Rif) using poly(α-lipoic acid) (pLA) and oligosaccharide (COS) to encapsulate Rif.
• Evaluation of cellular uptake and intracellular drug concentration compared to free Rif.
• Assessment of bacterial eradication in vitro and in vivo using bacteremia-bearing mouse models.

Main Results:

• PECs@Rif achieved 3.9 times higher Rif accumulation in the cytoplasm compared to free Rif.
• The complex facilitated Rif release and generated reactive oxygen species (ROS) via a Fenton reaction, enhancing bacterial killing.
• In vitro, PECs@Rif reduced intracellular bacteria by 2.8 orders of magnitude, significantly outperforming free Rif (0.7 orders of magnitude).
• In vivo studies showed substantial reductions in bacterial load in the liver, spleen, and kidney of treated mice.

Conclusions:

• Direct cytosolic delivery of Rif via PECs@Rif, mediated by thiol uptake, offers a promising strategy for treating intracellular bacterial infections.
• The combined action of enhanced drug delivery and ROS-induced oxidative stress significantly improves antibacterial efficacy.
• This approach provides a feasible platform for developing advanced therapies against challenging intracellular pathogens.