Polymicrobial Interactions Induce Multidrug Tolerance in Staphylococcus aureus Through Energy Depletion

Area of Science:

• Microbiology
• Infectious Diseases
• Antimicrobial Resistance

Background:

• Staphylococcus aureus infections often relapse due to antibiotic-tolerant biofilms.
• Polymicrobial biofilms, involving S. aureus and Candida albicans, exhibit heightened tolerance to antibiotics, but mechanisms are unclear.

Purpose of the Study:

• To investigate the mechanisms behind increased antibiotic tolerance in S. aureus and C. albicans polymicrobial biofilms.
• To determine if nutrient deprivation and altered metabolic activity contribute to enhanced antibiotic tolerance.

Main Methods:

• Cultured S. aureus and C. albicans in monocultures and polymicrobial biofilms.
• Assessed antibiotic tolerance to various drugs (oxacillin, vancomycin, ciprofloxacin, delafloxacin, rifampicin).
• Measured glucose availability, extracellular glucose, TCA cycle activity (fumarase expression), membrane potential, and intracellular ATP concentrations.

Main Results:

• Polymicrobial biofilms were 10- to 100-fold more tolerant to antibiotics than monocultures.
• Antibiotics diffused through polymicrobial biofilms, ruling out physical blockage.
• Polymicrobial cultures depleted glucose faster, showing decreased S. aureus TCA cycle activity and fumarase expression.
• S. aureus in polymicrobial cultures had reduced membrane potential and lower intracellular ATP levels.

Conclusions:

• Nutrient deprivation and decreased metabolic activity are key mechanisms for increased antibiotic tolerance in S. aureus and C. albicans polymicrobial biofilms.
• Understanding these mechanisms can inform strategies to combat relapsing biofilm infections.