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Download Hi-Res ImageDownload to MS-PowerPointCite This:ACS Infect. Dis. 2019, 5, 3, 473-483
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Development of Fungal Selective Amphiphilic Kanamycin: Cost-Effective Synthesis and Use of Fluorescent Analogs for Mode of Action Investigation

  • Yagya Prasad Subedi
    Yagya Prasad Subedi
    Department of Chemistry and Biochemistry, Utah State University, 0300 Old Main Hill, Logan, Utah 84322-0300, United States
    More by Yagya Prasad Subedi
    • , 
  • Paul Roberts
    Paul Roberts
    Department of Chemistry and Biochemistry, Utah State University, 0300 Old Main Hill, Logan, Utah 84322-0300, United States
    More by Paul Roberts
    • , 
  • Michelle Grilley
    Michelle Grilley
    Department of Biology, Utah State University, 5305 Old Main Hill, Logan, Utah 84322-5305, United States
    More by Michelle Grilley
    • , 
  • Jon Y. Takemoto
    Jon Y. Takemoto
    Department of Biology, Utah State University, 5305 Old Main Hill, Logan, Utah 84322-5305, United States
    More by Jon Y. Takemoto
    • , and 
  • Cheng-Wei Tom Chang*
    Cheng-Wei Tom Chang
    Department of Chemistry and Biochemistry, Utah State University, 0300 Old Main Hill, Logan, Utah 84322-0300, United States
    *E-mail: [email protected]
    More by Cheng-Wei Tom Chang
    Orcidhttp://orcid.org/0000-0002-8978-4520
Cite this: ACS Infect. Dis. 2019, 5, 3, 473–483
Publication Date (Web):January 23, 2019
https://doi.org/10.1021/acsinfecdis.8b00327
Copyright © 2019 American Chemical Society
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Abstract

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Amphiphilic aminoglycosides have attracted interest due to their novel antifungal activities. A crucial but often neglected factor for drug development in academia is cost of production. Herein is reported a one-step, inexpensive synthesis of amphiphilic alkyl kanamycins constituted with only natural components. The synthetic methodology also enabled the preparation of a series fluorescent amphiphilic aryl kanamycins for direct structure–activity mode of action studies. The lead compounds showed prominent antifungal activities against a panel of fungi, including Fusarium graminearum, Cryptococcus neoformans, and several Candida sp., and also significant antibacterial activities. With fluorescence-based whole cell assays, the aryl amphiphilic kanamycins were observed to permeabilize fungal surface membranes at faster rates than bacterial surface membranes. Also, the antifungal action of the amphiphilic kanamycins was observed to occur in a biphasic mode with an initial fast phase correlated with rapid membrane permeabilization at subminimal inhibitory concentrations and a slower phase membrane permeabilization that elevates the reactive oxygen species production leading to cell death. Inactive hydrophobic amphiphilic kanamycins displayed no membrane permeabilization. The results offer cost-effective methods for producing amphiphilic kanamycins and reveal insights into how nonfungal specific amphiphilic kanamycins can be employed for fungal specific diagnostic and therapeutic applications.

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsinfecdis.8b00327.

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Cited By

This article is cited by 5 publications.

  1. Ragini Gupta, Jyoti Thakur, Sanjay Pal, Deepakkumar Mishra, Parul Rani, Sandeep Kumar, Amandeep Saini, Archana Singh, Kavita Yadav, Aasheesh Srivastava, Rajendra Prasad, Siddhi Gupta, Avinash Bajaj. Cholic-Acid-Derived Amphiphiles Can Prevent and Degrade Fungal Biofilms. ACS Applied Bio Materials 2020, Article ASAP.
  2. Kaitlind C. Howard, Emily K. Dennis, David S. Watt, Sylvie Garneau-Tsodikova. A comprehensive overview of the medicinal chemistry of antifungal drugs: perspectives and promise. Chemical Society Reviews 2020, 49 (8) , 2426-2480. https://doi.org/10.1039/C9CS00556K
  3. K.V.S. Mani Chandrika, Sahida Sharma. Promising antifungal agents: A minireview. Bioorganic & Medicinal Chemistry 2020, 28 (7) , 115398. https://doi.org/10.1016/j.bmc.2020.115398
  4. Yagya Prasad Subedi, Uddav Pandey, Madher N. Alfindee, Heath Montgomery, Paul Roberts, Jeffrey Wight, Gavin Nichols, Michell Grilley, Jon Y. Takemoto, Cheng-Wei Tom Chang. Scalable and cost-effective tosylation-mediated synthesis of antifungal and fungal diagnostic 6″-Modified amphiphilic kanamycins. European Journal of Medicinal Chemistry 2019, 182 , 111639. https://doi.org/10.1016/j.ejmech.2019.111639
  5. Madher N. Alfindee, Yagya P. Subedi, Michelle M. Grilley, Jon Y. Takemoto, Cheng-Wei T. Chang. Antifungal Activities of 4″,6″-Disubstituted Amphiphilic Kanamycins. Molecules 2019, 24 (10) , 1882. https://doi.org/10.3390/molecules24101882

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