On-Site Serine Delivery Drives Fermentation Pathway Reprogramming to Reverse Intracellular Staphylococcus aureus...

Area of Science:

• Nanomedicine
• Microbiology
• Infectious Diseases

Background:

• Intracellular Staphylococcus aureus persisters are difficult to eradicate with antibiotics due to host-imposed nutrient deprivation.
• Conventional antibiotic treatments are ineffective against these resilient bacterial forms, contributing to recurrent infections.

Purpose of the Study:

• To develop a nanodrug delivery system for sensitizing intracellular Staphylococcus aureus persisters to antibiotics.
• To investigate the efficacy of on-site serine delivery in reversing bacterial persistence and enhancing antibiotic treatment.

Main Methods:

• Development of FAlsBm@Rif, a poly(amino acid)-based nanodrug encapsulating rifampicin and functionalized with serine and mannose.
• Utilizing mannose-mediated endocytosis for macrophage uptake and a cascade-targeting mechanism to deliver serine and rifampicin to intracellular persisters.
• Assessing the metabolic shift in persisters, including ATP production and membrane potential, and evaluating in vivo eradication rates.

Main Results:

• FAlsBm@Rif successfully delivered serine and rifampicin to intracellular Staphylococcus aureus persisters within macrophages.
• On-site serine delivery promoted a metabolic shift to fermentation, boosting ATP production and reversing persistence.
• In vivo studies showed FAlsBm@Rif eradicated 99.78% of intracellular persisters, significantly outperforming rifampicin alone (63.41%).

Conclusions:

• FAlsBm@Rif demonstrates a promising strategy for combating intracellular Staphylococcus aureus persisters by overcoming host-imposed nutrient deprivation.
• The nanodrug's cascade-targeting mechanism ensures precise delivery and localized serine release, effectively reversing bacterial persistence.
• This approach offers a potential solution for recurrent infections caused by antibiotic-tolerant persister cells.