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High-throughput Screening for Broad-spectrum Chemical Inhibitors of RNA Viruses
Published on: May 5, 2014
Broad-spectrum antifungal activity of C12/C14 alkyl triphenylphosphonium salts (TPP-C12 and TPP-C14) against
Yuanyuan Geng1,2, Xiaohui Wang3, Shu Zhang1,2
1National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.
Introduction:
Human fungal infections affect billions of people and result in more than 2 million deaths every year, however, they have historically been neglected as a cause of infectious disease-related deaths worldwide. Fungal drug resistance has become an increasingly serious problem with the wide use of antifungal drugs and the adaptive evolution of fungi. Resistance to all commonly used antifungal drugs has been reported, and the development of non-traditional antifungal drugs is urgently needed.
Methods:
Minimal inhibitory concentrations (MICs) of clinical pathogenic fungi were assessed by broth dilution antifungal susceptibility testing. One hundred and twenty eight yeast strains and 66 filamentous strains were used, including C. albicans resistant and susceptible to azoles, C. tropicalis, C. auris, C. krusei, the C. glabrata complex, the C. haemulonii complex, the C. parapsilosis complex, Cryptococcus neoformans, Aspergillum, Trichophyton, and dimorphic Sporothrix globosa. Further RNAseq was performed to explore the antifungal mechanism of two derivatives.
Results:
Two derivatives of the mitochondrion-targeted compound triphenylphosphonium (TPP), TPP-C12 and TPP-C14, showed broad-spectrum antifungal activity. The MIC against yeast strains was 1.5173 and 1.0109 mg/L, respectively. For filamentous strains, the MIC ranges were 2-8 mg/L for both compounds. For the dimorphic Sporothrix globosa, the GM values were 1.0134 and 1.0816 mg/L, respectively. RNAseq revealed that the derivatives interfered with mainly mitochondrial and ribosomal functions. Through coregulation of mitochondrial and nuclear genes, the derivatives cause mitochondrial dysfunction and ultimately cell death.
Discussion:
Taken together, the findings show that TPP-C12 and TPP-C14 are stable, effective, and broad-spectrum antifungal agents with no species or strain specificity.
Insights
New mitochondrion-targeted compounds, TPP-C12 and TPP-C14, demonstrate broad-spectrum antifungal activity against diverse fungal pathogens. These stable and effective agents offer a promising alternative to traditional antifungals, addressing the growing problem of drug resistance.
Area of Science:
- Mycology
- Medicinal Chemistry
- Antimicrobial Resistance
Background:
- Human fungal infections cause millions of deaths annually and are often neglected.
- Antifungal drug resistance is a growing global health concern, necessitating novel therapeutic agents.
- Traditional antifungal drugs face challenges due to resistance development in fungal pathogens.
Purpose of the Study:
- To evaluate the antifungal activity of two novel mitochondrion-targeted triphenylphosphonium (TPP) derivatives, TPP-C12 and TPP-C14.
- To investigate the antifungal mechanisms of action for these TPP derivatives.
- To assess the broad-spectrum efficacy of TPP-C12 and TPP-C14 against various clinical fungal isolates.
Main Methods:
- Broth dilution antifungal susceptibility testing was performed on 128 yeast and 66 filamentous fungal strains.
- A diverse panel of pathogenic fungi was tested, including azole-resistant C. albicans, C. auris, C. neoformans, and Aspergillus species.
- RNA sequencing (RNAseq) was employed to elucidate the molecular mechanisms underlying the antifungal activity.
Main Results:
- TPP-C12 and TPP-C14 exhibited broad-spectrum antifungal activity against all tested yeast and filamentous fungi.
- Minimal inhibitory concentrations (MICs) for yeast strains ranged from 1.0109 to 1.5173 mg/L, and for filamentous strains, from 2-8 mg/L.
- RNAseq analysis revealed that the compounds disrupt mitochondrial and ribosomal functions, leading to cell death through coregulation of nuclear and mitochondrial genes.
Conclusions:
- TPP-C12 and TPP-C14 are stable, effective, and broad-spectrum antifungal agents.
- These novel compounds demonstrate significant potential as non-traditional antifungal drugs.
- The findings suggest TPP-C12 and TPP-C14 possess no species or strain specificity, offering a promising therapeutic avenue.
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