title: Aryl-alkyl-lysines: Membrane-Active Fungicides That Act against Biofilms of Candida albicans.
abstract: Mortality due to pathogenic fungi has been exacerbated by the rapid development of resistance to frontline antifungal drugs. Fungicidal compounds with novel mechanisms of action are urgently needed. Aryl-alkyl-lysines, which are membrane-active small molecules, were earlier shown to be broad-spectrum antibacterial agents with potency in vitro and in vivo. Herein, we report the antifungal properties of aryl-alkyl-lysines. After identifying the most active compound (NCK-10), we tested its activity against a panel of clinically relevant pathogenic fungi and examined NCK-10's effect against immature and mature biofilms of Candida albicans. NCK-10 was capable of inhibiting the growth of various species of fungi (including Candida spp., Cryptococcus spp., and Aspergillus fumigatus) at concentrations similar to those of antifungal drugs used clinically. It was observed that polarization and permeability of the fungal cell membrane were compromised upon addition of NCK-10, indicating its mechanism is disruption of the fungal cell membrane. In addition to interfering with the growth of planktonic fungi, NCK-10 demonstrated the ability to both inhibit biofilm formation and reduce the metabolic activity of cells in C. albicans biofilm. Additionally, our compound was capable of crossing the blood-brain barrier in an in vitro model, expanding the potential antifungal applications for NCK-10. Overall, aryl-alkyl-lysines were found to be excellent compounds that warrant further investigation as novel antifungal agents.
authors.affiliation: Chemical Biology and Medicinal Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research , Jakkur, Bangalore, Karnataka 560064, India.
authors.forename: Chandradhish
authors.initials: C
authors.lastname: Ghosh
authors.affiliation: Molecular Mycology Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research , Jakkur, Bangalore, Karnataka 560064, India.
authors.forename: Vikas
authors.initials: V
authors.lastname: Yadav
authors.affiliation: Department of Comparative Pathobiology, Purdue University , 625 Harrison Street, West Lafayette, Indiana 47907, United States.
authors.forename: Waleed
authors.initials: W
authors.lastname: Younis
authors.affiliation: Department of Comparative Pathobiology, Purdue University , 625 Harrison Street, West Lafayette, Indiana 47907, United States.
authors.forename: Haroon
authors.identifier: 0000-0002-8843-8933
authors.initials: H
authors.lastname: Mohammad
authors.affiliation: Department of Comparative Pathobiology, Purdue University , 625 Harrison Street, West Lafayette, Indiana 47907, United States.
authors.forename: Youssef A
authors.initials: YA
authors.lastname: Hegazy
authors.affiliation: Department of Comparative Pathobiology, Purdue University , 625 Harrison Street, West Lafayette, Indiana 47907, United States.|Purdue Institute for Inflammation, Immunology, and Infectious Disease, Purdue University , West Lafayette, Indiana 47907, United States.
authors.forename: Mohamed N
authors.initials: MN
authors.lastname: Seleem
authors.affiliation: Molecular Mycology Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research , Jakkur, Bangalore, Karnataka 560064, India.
authors.forename: Kaustuv
authors.initials: K
authors.lastname: Sanyal
authors.affiliation: Chemical Biology and Medicinal Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research , Jakkur, Bangalore, Karnataka 560064, India.
authors.forename: Jayanta
authors.identifier: 0000-0002-8068-1015
authors.initials: J
authors.lastname: Haldar
mesh_terms: D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects*; D002176:Candida albicans / Q000187:drug effects / Q000502:physiology*; D002462:Cell Membrane / Q000187:drug effects; D002463:Cell Membrane Permeability / Q000187:drug effects; D006801:Humans; D008826:Microbial Sensitivity Tests; D057786:Peptidomimetics
chemical_list: D000935:Antifungal Agents; D057786:Peptidomimetics
keywords: antifungal drugs; antimicrobial peptides; fungal biofilms; peptidomimetics