Modulation of Azithromycin Activity against Single-Species and Binary Biofilms of Staphylococcus aureus and Kytococcus schroeteri by Norepinephrine

Abstract The effect of norepinephrine as a compound modulating the activity of the antibiotic azithromycin on single-species and binary biofilms of members of the human microbiota, Staphylococcus aureus and Kytococcus schroeteri, was studied in various model systems. At the concentration of 3.55 µM, the hormone was shown to be able, depending on the cultivation system and incubation time, of both enhancing and weakening the effects of azithromycin at subinhibitory concentrations (0.001 and 4 µg/mL). In the case of rapidly formed biofilms, norepinephrine weakened the inhibitory effect of the antibiotic, while in the presence of the full stage of adhesion the hormone, on the contrary, enhanced the inhibitory effect. Interaction between two microorganisms in the community was no less important, since the presence of K. schroeteri in the community changed the effect of azithromycin (4 μg/mL) in combination with norepinephrine on S. aureus . It was shown that azithromycin and norepinephrine, as well as their combinations, were able to change the expression of the genes coding resistance not only to macrolides (increased expression of the mrx gene by a combination of 4 μg/mL azithromycin and 3.55 μM norepinephrine), but also to fluoroquinolones (decreased expression of the arlR gene and increased one of mdtK ).