Overcoming Acquired and Native Macrolide Resistance with Bicarbonate

Area of Science:

• Microbiology
• Infectious Diseases
• Pharmacology

Background:

• Microbial resistance to antibiotics is a significant global health challenge.
• Macrolide antibiotics are crucial for treating severe bacterial infections but face resistance issues.
• New strategies are needed to restore the efficacy of existing antibiotics.

Purpose of the Study:

• To investigate bicarbonate as an enhancer of macrolide antibiotic activity.
• To determine if bicarbonate can overcome acquired and intrinsic macrolide resistance.
• To evaluate bicarbonate's potential in treating bacterial infections caused by resistant pathogens.

Main Methods:

• Tested bicarbonate's effect on azithromycin activity against clinically relevant pathogens.
• Assessed bicarbonate's role in increasing intracellular azithromycin concentrations.
• Evaluated topical azithromycin with bicarbonate in a *Pseudomonas aeruginosa* wound infection model in mice.
• Examined bicarbonate's effect on azithromycin efficacy against methicillin-resistant *Staphylococcus aureus* (MRSA) in a systemic infection model in mice.

Main Results:

• Physiological bicarbonate concentrations significantly enhance macrolide antibiotic activity.
• Bicarbonate overcomes both acquired and intrinsic macrolide resistance mechanisms.
• Bicarbonate increases intracellular azithromycin concentration, improving efficacy.
• Demonstrated efficacy of bicarbonate-enhanced azithromycin in murine models of wound and systemic infections.

Conclusions:

• Bicarbonate is a potent enhancer of macrolide antibiotics, capable of overcoming drug resistance.
• Observed macrolide resistance in laboratory settings may not accurately predict clinical efficacy.
• Bicarbonate holds potential as a formulation additive or host factor to combat drug-resistant bacterial infections.