Antiplasmodial peptaibols act through membrane directed mechanisms

Jennifer E Collins; Jin Woo Lee; Frances Rocamora; Gagandeep S Saggu; Karen L Wendt; Charisse Flerida A Pasaje; Sebastian Smick; Natalia Mojica Santos; Raphaella Paes; Tiantian Jiang; Nimisha Mittal; Madeline R Luth; Taylor Chin; Howard Chang; James L McLellan; Beatriz Morales-Hernandez; Kirsten K Hanson; Jacquin C Niles; Sanjay A Desai; Elizabeth A Winzeler; Robert H Cichewicz; Debopam Chakrabarti

doi:10.1016/j.chembiol.2023.10.025

Antiplasmodial peptaibols act through membrane directed mechanisms

Cell Chem Biol. 2024 Feb 15;31(2):312-325.e9. doi: 10.1016/j.chembiol.2023.10.025. Epub 2023 Nov 22.

Authors

Jennifer E Collins¹, Jin Woo Lee², Frances Rocamora³, Gagandeep S Saggu⁴, Karen L Wendt², Charisse Flerida A Pasaje⁵, Sebastian Smick⁵, Natalia Mojica Santos¹, Raphaella Paes¹, Tiantian Jiang³, Nimisha Mittal³, Madeline R Luth³, Taylor Chin³, Howard Chang³, James L McLellan⁶, Beatriz Morales-Hernandez⁶, Kirsten K Hanson⁶, Jacquin C Niles⁵, Sanjay A Desai⁴, Elizabeth A Winzeler⁷, Robert H Cichewicz⁸, Debopam Chakrabarti⁹

Affiliations

¹ Burnett School of Biomedical Sciences, University of Central Florida, Orlando, FL 32826, USA.
² Department of Chemistry and Biochemistry, Institute for Natural Products Applications & Research Technologies, University of Oklahoma, Norman OK 73019, USA.
³ Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA.
⁴ Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, NIH, Rockville, MD 20852, USA.
⁵ Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
⁶ Department of Molecular Microbiology and Immunology and South Texas Center for Emerging Infectious Diseases, University of Texas San Antonio, San Antonio, TX 78249, USA.
⁷ 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.
⁸ Department of Chemistry and Biochemistry, Institute for Natural Products Applications & Research Technologies, University of Oklahoma, Norman OK 73019, USA. Electronic address: rhcichewicz@ou.edu.
⁹ Burnett School of Biomedical Sciences, University of Central Florida, Orlando, FL 32826, USA. Electronic address: dchak@ucf.edu.

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.

Keywords: AMPs; Alamethicin; MDR1; Plasmodium; antiplasmodial; digestive vacuole; ion channel; malaria; peptaibol; peptides.

MeSH terms

Antimalarials* / pharmacology
Cell Membrane Permeability
Humans
Malaria, Falciparum*
Membrane Transport Proteins
Peptaibols / metabolism
Peptaibols / pharmacology

Substances

Peptaibols
Antimalarials
Membrane Transport Proteins

Abstract

MeSH terms

Substances

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