Decline in nitrosative stress drives antibiotic persister regrowth during infection

Area of Science:

• Microbiology
• Immunology
• Bacterial Pathogenesis

Background:

• Macrophage internalization of pathogenic bacteria leads to antibiotic-tolerant persister cells.
• Persister cell regrowth is a key factor in infection relapse after antibiotic treatment cessation.
• The signals governing persister regrowth during infection remain poorly understood.

Purpose of the Study:

• To elucidate the mechanisms and signals controlling persister cell regrowth within macrophages.
• To investigate the role of host-derived factors in maintaining bacterial persister dormancy.
• To identify potential therapeutic targets for preventing infection relapse.

Main Methods:

• Investigated persister formation and regrowth dynamics in macrophages following Salmonella infection.
• Analyzed the impact of host reactive nitrogen species (RNS) on bacterial TCA cycle function and ATP production.
• Utilized RNS production inhibitors to modulate persister regrowth during antibiotic treatment.

Main Results:

• Host RNS produced during Salmonella infection arrest persisters by inhibiting their TCA cycle, reducing respiration and ATP.
• Intracellular persisters resume growth upon subsidence of macrophage RNS production and restoration of TCA cycle function.
• Persister regrowth is slow and heterogeneous, prolonging the reservoir for infection relapse.
• Inhibiting RNS production during antibiotic treatment promotes persister regrowth, enhancing eradication.

Conclusions:

• Host RNS are critical regulators of bacterial persister dormancy within macrophages.
• Targeting RNS production offers a novel strategy to overcome antibiotic tolerance and prevent infection relapse.
• Understanding persister regrowth mechanisms is crucial for developing effective anti-infective therapies.