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

Yongting Zhang,Qiu Meng,Haichun Gao,Kailun Guo

doi:10.1038/s42003-020-0991-4

Abstract

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.

Highlights

IntroductionNitrite has been used in food preservation for centuries. When used in combination with antibiotics, nitrite is reported to work either cooperatively or antagonistically
As a bacteriostatic agent, nitrite has been used in food preservation for centuries
To test whether this phenomenon is common among bacteria, in this study we examined impacts of nitrite on aminoglycoside tolerance in S. oneidensis, E. coli, B. subtilis, and S. aureus, along with P. aeruginosa as the control

Summary

Introduction

Nitrite has been used in food preservation for centuries. When used in combination with antibiotics, nitrite is reported to work either cooperatively or antagonistically. Nitrite has been found to be either cooperative or antagonistic when used in combination with antibiotics in Pseudomonas aeruginosa[8,10,11] These effects are a result of the bacteriostatic action, which does not require NO as an intermediate[1]. Tolerance induced by nitrite to aminoglycosides and Cip is proposed to be attributed to impaired respiration (oxygen consumption rate, hereafter referred to as respiration) given similar effects of other respiratory inhibitors, such as cyanide and carbonyl cyanide m-chlorophenylhydrazone (CCCP)[10,11]. Reduced respiration likely compromises PMF formation, the direct evidence is lacking Despite these findings, the antimicrobial mechanisms of nitrite, especially those through which respiration and/or PMF are impaired, is only partially understood[11]

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