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Antiplasmodial peptaibols act through membrane directed mechanisms.
Collins, Jennifer E; Lee, Jin Woo; Rocamora, Frances; Saggu, Gagandeep S; Wendt, Karen L; Pasaje, Charisse Flerida A; Smick, Sebastian; Santos, Natalia Mojica; Paes, Raphaella; Jiang, Tiantian; Mittal, Nimisha; Luth, Madeline R; Chin, Taylor; Chang, Howard; McLellan, James L; Morales-Hernandez, Beatriz; Hanson, Kirsten K; Niles, Jacquin C; Desai, Sanjay A; Winzeler, Elizabeth A; Cichewicz, Robert H; Chakrabarti, Debopam.
Afiliación
  • Collins JE; Burnett School of Biomedical Sciences, University of Central Florida, Orlando, FL 32826, USA.
  • Lee JW; Department of Chemistry and Biochemistry, Institute for Natural Products Applications & Research Technologies, University of Oklahoma, Norman OK 73019, USA.
  • Rocamora F; Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA.
  • Saggu GS; Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, NIH, Rockville, MD 20852, USA.
  • Wendt KL; Department of Chemistry and Biochemistry, Institute for Natural Products Applications & Research Technologies, University of Oklahoma, Norman OK 73019, USA.
  • Pasaje CFA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
  • Smick S; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
  • Santos NM; Burnett School of Biomedical Sciences, University of Central Florida, Orlando, FL 32826, USA.
  • Paes R; Burnett School of Biomedical Sciences, University of Central Florida, Orlando, FL 32826, USA.
  • Jiang T; Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA.
  • Mittal N; Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA.
  • Luth MR; Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA.
  • Chin T; Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA.
  • Chang H; Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA.
  • McLellan JL; Department of Molecular Microbiology and Immunology and South Texas Center for Emerging Infectious Diseases, University of Texas San Antonio, San Antonio, TX 78249, USA.
  • Morales-Hernandez B; Department of Molecular Microbiology and Immunology and South Texas Center for Emerging Infectious Diseases, University of Texas San Antonio, San Antonio, TX 78249, USA.
  • Hanson KK; Department of Molecular Microbiology and Immunology and South Texas Center for Emerging Infectious Diseases, University of Texas San Antonio, San Antonio, TX 78249, USA.
  • Niles JC; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
  • Desai SA; Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, NIH, Rockville, MD 20852, USA.
  • Winzeler EA; Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA. Electronic address: ewinzeler@health.ucsd.edu.
  • Cichewicz RH; Department of Chemistry and Biochemistry, Institute for Natural Products Applications & Research Technologies, University of Oklahoma, Norman OK 73019, USA. Electronic address: rhcichewicz@ou.edu.
  • Chakrabarti D; Burnett School of Biomedical Sciences, University of Central Florida, Orlando, FL 32826, USA. Electronic address: dchak@ucf.edu.
Cell Chem Biol ; 31(2): 312-325.e9, 2024 Feb 15.
Article en En | MEDLINE | ID: mdl-37995692
ABSTRACT
Our previous study identified 52 antiplasmodial peptaibols isolated from fungi. To understand their antiplasmodial mechanism of action, we conducted phenotypic assays, assessed the in vitro evolution of resistance, and performed a transcriptome analysis of the most potent peptaibol, HZ NPDG-I. HZ NPDG-I and 2 additional peptaibols were compared for their killing action and stage dependency, each showing a loss of digestive vacuole (DV) content via ultrastructural analysis. HZ NPDG-I demonstrated a stepwise increase in DV pH, impaired DV membrane permeability, and the ability to form ion channels upon reconstitution in planar membranes. This compound showed no signs of cross resistance to targets of current clinical candidates, and 3 independent lines evolved to resist HZ NPDG-I acquired nonsynonymous changes in the P. falciparum multidrug resistance transporter, pfmdr1. Conditional knockdown of PfMDR1 showed varying effects to other peptaibol analogs, suggesting differing sensitivity.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Malaria Falciparum / Antimaláricos Límite: Humans Idioma: En Revista: Cell Chem Biol Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Malaria Falciparum / Antimaláricos Límite: Humans Idioma: En Revista: Cell Chem Biol Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos