Nitroxoline exerts potent anti-Aspergillus fumigatus activity by disrupting copper homeostasis and inducing oxidative

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Yiru Zhang1,2, Yuxin Han1,2, Dan Cao1,2

  • 1State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, China-Singapore Belt and Road Joint Laboratory on Infection Research and Drug Development, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.

Antimicrobial Agents and Chemotherapy
|March 31, 2026
PubMed

Insights

Nitroxoline (NTX) shows strong antifungal activity against Aspergillus fumigatus, effectively treating invasive pulmonary aspergillosis (IPA) in a mouse model. This drug targets copper homeostasis, offering a new strategy against resistant fungal infections.

Area of Science:

  • Mycology
  • Pharmacology
  • Infectious Diseases

Background:

  • Invasive pulmonary aspergillosis (IPA) presents a significant clinical challenge due to limited treatment options and increasing antifungal resistance.
  • Aspergillus fumigatus is a primary cause of IPA, necessitating the development of novel therapeutic agents.

Purpose of the Study:

  • To evaluate the antifungal potential and mechanism of action of nitroxoline (NTX), an 8-hydroxyquinoline derivative, against Aspergillus fumigatus.
  • To investigate NTX's efficacy in an established invasive pulmonary aspergillosis mouse model.

Main Methods:

  • In vitro susceptibility testing against 64 clinical isolates and the AF293 reference strain of Aspergillus fumigatus.
  • Assessment of NTX's impact on conidial maturation, survival rates, pulmonary fungal burden, lung inflammation, and hyphal invasion in a mouse model of IPA.
  • Transcriptomic analysis to elucidate the molecular mechanism of NTX action, focusing on copper homeostasis and oxidative stress pathways.

Main Results:

  • Nitroxoline demonstrated potent in vitro antifungal activity, delaying conidial maturation.
  • In vivo studies showed NTX significantly improved survival, reduced fungal burden, and alleviated lung inflammation in the IPA mouse model.
  • Transcriptomic data indicated NTX disrupts the copper homeostasis-oxidative stress axis by downregulating the copper transporter ctrC and superoxide dismutase sodB.

Conclusions:

  • Nitroxoline exerts significant anti-Aspergillus fumigatus effects both in vitro and in vivo.
  • The mechanism involves perturbing copper homeostasis and inducing oxidative stress, offering a novel therapeutic approach.
  • NTX highlights the potential of metal-targeted strategies for treating IPA and drug-resistant fungal infections.
Keywords:
Aspergillus fumigatusROSantifungal activitycopper homeostasisnitroxoline

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