Nitric oxide (NO) elicits aminoglycoside tolerance in Escherichia coli but antibiotic resistance gene carriage and NO sensitivity have not co-evolved

Ribiero, C; Rahman, LA; Holmes, LG; Woody, AM; Webster, CM; Monaghan, TI; Robinson, GK; Mühlschlegel, FA; Goodhead, IB; Shepherd, M

Abstract

The spread of multidrug-resistance in Gram-negative bacterial pathogens presents a major clinical challenge, and new approaches are required to combat these organisms. Nitric oxide (NO) is a well-known antimicrobial that is produced by the immune system in response to infection, and numerous studies have demonstrated that NO is a respiratory inhibitor with both bacteriostatic and bactericidal properties. However, given that loss of aerobic respiratory complexes is known to diminish antibiotic efficacy, it was hypothesised that the potent respiratory inhibitor NO would elicit similar effects. Indeed, the current work demonstrates that pre-exposure to NO-releasers elicits a >10-fold increase in IC50 for gentamicin against pathogenic E. coli (i.e. a huge decrease in lethality). It was therefore hypothesised that hyper-sensitivity to NO may have arisen in bacterial pathogens, and that this trait could promote the acquisition of antibiotic-resistance mechanisms through enabling cells to persist in the presence of toxic levels of antibiotic. To test this hypothesis, genomics and microbiological approaches were used to screen a collection of E. coli clinical isolates for antibiotic susceptibility and NO tolerance, although the data did not support a correlation between increased carriage of antibiotic resistance genes and NO tolerance. However, the current work has important implications for how antibiotic susceptibility might be measured in future (i.e. +/- NO), and underlines the evolutionary advantage for bacterial pathogens to maintain tolerance to toxic levels of NO.

Citation

Ribiero, C., Rahman, L., Holmes, L., Woody, A., Webster, C., Monaghan, T., …Shepherd, M. (2021). Nitric oxide (NO) elicits aminoglycoside tolerance in Escherichia coli but antibiotic resistance gene carriage and NO sensitivity have not co-evolved. Archives of Microbiology, 203(5), 2541-2550. https://doi.org/10.1007/s00203-021-02245-2

• Journal Article Type: Article
• Acceptance Date: Feb 14, 2021
• Online Publication Date: Mar 7, 2021
• Publication Date: Jul 1, 2021
• Deposit Date: Dec 10, 2020
• Publicly Available Date: Mar 22, 2021
• Journal: Archives of Microbiology
• Print ISSN: 0302-8933
• Electronic ISSN: 1432-072X
• Publisher: Springer Verlag
• Volume: 203
• Issue: 5
• Pages: 2541-2550
• DOI: https://doi.org/10.1007/s00203-021-02245-2
• Publisher URL: https://doi.org/10.1007/s00203-021-02245-2
• Related Public URLs: http://link.springer.com/journal/203
• Additional Information: Funders : Strategic Research Development Fund (KentHealth);University of Salford Research Support fund