Understanding and Sensitizing Density-Dependent Persistence to Quinolone Antibiotics

Area of Science:

• Microbiology
• Molecular Biology
• Biochemistry

Background:

• Antibiotic treatment faces challenges from physiological and environmental factors affecting drug activity.
• Quinolone antibiotics, targeting bacterial topoisomerases, are ineffective against high-density bacterial cultures, a phenomenon termed persistence.
• The underlying mechanisms of this growth phase-dependent antibiotic persistence remain largely unknown.

Purpose of the Study:

• To elucidate the mechanistic basis for quinolone antibiotic persistence in high-density bacterial cultures.
• To identify metabolic factors contributing to bacterial resistance to quinolone antibiotics.
• To develop a strategy for sensitizing non-dividing bacteria to quinolone killing.

Main Methods:

• Investigated the link between bacterial metabolism and quinolone efficacy in stationary-phase cultures.
• Supplemented high-density cultures of Escherichia coli, Staphylococcus aureus, and Mycobacterium smegmatis with glucose and terminal electron acceptors.
• Assessed the impact of metabolic stimulation on bacterial susceptibility to quinolone antibiotics.

Main Results:

• Exhaustion of metabolic inputs for oxidative phosphorylation is a key driver of quinolone persistence.
• Supplementation with glucose and a terminal electron acceptor restored sensitivity to quinolone antibiotics in high-density cultures.
• This metabolic intervention successfully sensitized diverse bacterial species, including E. coli, S. aureus, and M. smegmatis, to quinolone killing.

Conclusions:

• Bacterial persistence to quinolone antibiotics is directly linked to impairments in respiratory metabolism.
• Stimulating respiratory metabolism can overcome growth phase-dependent antibiotic resistance.
• This study provides a novel strategy to enhance the efficacy of quinolone antibiotics against non-dividing bacterial populations.