Overcoming Acquired and Native Macrolide Resistance with Bicarbonate

The
growing challenge of microbial resistance emphasizes the importance
of new antibiotics or reviving strategies for the use of old ones.
Macrolide antibiotics are potent bacterial protein synthesis inhibitors
with a formidable capacity to treat life-threatening bacterial infections;
however, acquired and intrinsic resistance limits their clinical application.
In the work presented here, we reveal that bicarbonate is a potent
enhancer of the activity of macrolide antibiotics that overcomes both
acquired and intrinsic resistance mechanisms. With a focus on azithromycin,
a highly prescribed macrolide antibiotic, and using clinically relevant
pathogens, we show that physiological concentrations of bicarbonate
overcome drug resistance by increasing the intracellular concentration
of azithromycin. We demonstrate the potential of bicarbonate as a
formulation additive for topical use of azithromycin in treating a
murine wound infection caused by Pseudomonas aeruginosa. Further, using a systemic murine model of methicillin-resistant Staphylococcus aureus (MRSA) infection, we demonstrate the
potential role of physiological bicarbonate, naturally abundant in
the host, to enhance the activity of azithromycin against macrolide-resistant
MRSA. In all, our findings suggest that macrolide resistance, observed
in the clinical microbiology laboratory using standard culturing techniques,
is a poor predictor of efficacy in the clinic and that observed resistance
should not necessarily hamper the use of macrolides. Whether as a
formulation additive for topical use or as a natural component of
host tissues, bicarbonate is a powerful potentiator of macrolides
with the capacity to overcome drug resistance in life-threatening
bacterial infections.