Intoxication of antibiotic persisters by host RNS inactivates their efflux machinery during infection

Area of Science:

• Microbiology
• Infectious Diseases
• Pharmacology

Background:

• Antibiotic efficacy is significantly influenced by the host environment during infection.
• Pathogen stresses can lead to the development of antibiotic-tolerant phenotypic variants known as persister cells.
• Persister cells are implicated in antibiotic treatment failure and recurrent infections.

Purpose of the Study:

• To investigate the impact of host reactive nitrogen species (RNS) on persister cell susceptibility to fluoroquinolone antibiotics.
• To elucidate the mechanisms by which RNS affect persister survival within host cells.
• To understand the contribution of efflux machinery to antibiotic tolerance in persister cells.

Main Methods:

• Studying Salmonella persisters within host cells.
• Assessing the effect of RNS on persister cell survival and antibiotic susceptibility.
• Analyzing the impact of RNS on bacterial respiration, proton-motive force, and efflux pump activity.

Main Results:

• Host RNS were found to collaterally sensitize persister cells to fluoroquinolones, enhancing antibiotic efficacy against intramacrophage Salmonella.
• RNS intoxication reduces bacterial respiration and proton-motive force.
• RNS inactivate the AcrAB efflux machinery, promoting intracellular accumulation of fluoroquinolones.

Conclusions:

• Bacterial persister survival against antibiotics during infection is not solely due to target inactivity but significantly involves active efflux mechanisms.
• Host-derived RNS can modulate persister physiology to increase susceptibility to certain antibiotics.
• Understanding host-pathogen-antibiotic interactions is crucial for optimizing antibiotic treatments for persistent infections.