Nitrite modulates aminoglycoside tolerance by inhibiting cytochrome heme-copper oxidase in bacteria.

As a bacteriostatic agent, nitrite has been used in food preservation for centuries. When used in combination with antibiotics, nitrite is reported to work either cooperatively or antagonistically. However, the mechanism underlying these effects remains largely unknown. Here we show that nitrite mediates tolerance to aminoglycosides in both Gram-negative and Gram-positive bacteria, but has little interaction with other types of antibiotics. Nitrite directly and mainly inhibits cytochrome heme-copper oxidases (HCOs), and by doing so, the membrane potential is compromised, blocking uptake of aminoglycosides. In contrast, reduced respiration (oxygen consumption rate) resulting from nitrite inhibition is not critical for aminoglycoside tolerance. While our data indicate that nitrite is a promising antimicrobial agent targeting HCOs, cautions should be taken when used with other antibiotics, aminoglycosides in particular. Zhang et al. show that nitrite mediates bacterial tolerance to aminoglycosides without affecting other antibiotics. They find that nitrite inhibits cytochrome heme-copper oxidases, blocking bacterial uptake of aminoglycosides. This study suggests nitrite as a promising antimicrobial agent while discouraging its combined use with aminoglycosides.