CpxA/R‐Controlled Nitroreductase Expression as Target for Combinatorial Therapy against Uropathogens by Promoting Reactive Oxygen Species Generation Article Swipe
Hao Ren
,
Zixing Zhong
,
Shuang Zhou
,
Yiyang Wei
,
Yu-jiao Liang
,
Huiling He
,
Zi‐Jian Zheng
,
Mengyuan Li
,
He Qian
,
Tengfei Long
,
Xin‐Lei Lian
,
Xiao‐Ping Liao
,
Yahong Liu
,
Jian Sun
·
YOU?
·
· 2023
· Open Access
·
· DOI: https://doi.org/10.1002/advs.202300938
YOU?
·
· 2023
· Open Access
·
· DOI: https://doi.org/10.1002/advs.202300938
The antibiotic resistances emerged in uropathogens lead to accumulative treatment failure and recurrent episodes of urinary tract infection (UTI), necessitating more innovative therapeutics to curb UTI before systematic infection. In the current study, the combination of amikacin and nitrofurantoin is found to synergistically eradicate Gram‐negative uropathogens in vitro and in vivo. The mechanistic analysis demonstrates that the amikacin, as an aminoglycoside, induced bacterial envelope stress by introducing mistranslated proteins, thereby constitutively activating the cpxA / R two‐component system (Cpx signaling). The activation of Cpx signaling stimulates the expression of bacterial major nitroreductases ( nfsA / nfsB ) through soxS / marA regulons. As a result, the CpxA/R ‐dependent nitroreductases overexpression generates considerable quantity of lethal reactive intermediates via nitroreduction and promotes the prodrug activation of nitrofurantoin. As such, these actions together disrupt the bacterial cellular redox balance with excessively‐produced reactive oxygen species (ROS) as “Domino effect”, accelerating the clearance of uropathogens. Although aminoglycosides are used as proof‐of‐principle to elucidate the mechanism, the synergy between nitrofurantoin is generally applicable to other Cpx stimuli. To summarize, this study highlights the potential of aminoglycoside‐nitrofurantoin combination to replenish the arsenal against recurrent Gram‐negative uropathogens and shed light on the Cpx signaling‐controlled nitroreductase as a potential target to manipulate the antibiotic susceptibility.
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Metadata
- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1002/advs.202300938
- https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/advs.202300938
- OA Status
- gold
- Cited By
- 10
- References
- 83
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4383215148
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
-
https://openalex.org/W4383215148Canonical identifier for this work in OpenAlex
- DOI
-
https://doi.org/10.1002/advs.202300938Digital Object Identifier
- Title
-
CpxA/R‐Controlled Nitroreductase Expression as Target for Combinatorial Therapy against Uropathogens by Promoting Reactive Oxygen Species GenerationWork title
- Type
-
articleOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2023Year of publication
- Publication date
-
2023-07-05Full publication date if available
- Authors
-
Hao Ren, Zixing Zhong, Shuang Zhou, Yiyang Wei, Yu-jiao Liang, Huiling He, Zi‐Jian Zheng, Mengyuan Li, He Qian, Tengfei Long, Xin‐Lei Lian, Xiao‐Ping Liao, Yahong Liu, Jian SunList of authors in order
- Landing page
-
https://doi.org/10.1002/advs.202300938Publisher landing page
- PDF URL
-
https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/advs.202300938Direct link to full text PDF
- Open access
-
YesWhether a free full text is available
- OA status
-
goldOpen access status per OpenAlex
- OA URL
-
https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/advs.202300938Direct OA link when available
- Concepts
-
Nitroreductase, Reactive oxygen species, Aminoglycoside, Antibiotics, Microbiology, Chemistry, Nitrofurantoin, Prodrug, Biology, Pharmacology, Antibiotic resistance, BiochemistryTop concepts (fields/topics) attached by OpenAlex
- Cited by
-
10Total citation count in OpenAlex
- Citations by year (recent)
-
2025: 4, 2024: 5, 2023: 1Per-year citation counts (last 5 years)
- References (count)
-
83Number of works referenced by this work
- Related works (count)
-
10Other works algorithmically related by OpenAlex
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