Flippase Inhibitors as Antimicrobial Agents

Author

Robert Tancer, Seton Hall UniversityFollow

Date of Award

Spring 5-21-2022

Degree Type

Dissertation

Degree Name

PhD. Chemistry

Department

Chemistry and Biochemistry

Advisor

Gregory Wiedman, Ph.D.

Committee Member

Wyatt Murphy, Ph.D.

Committee Member

Cecilia Marzabadi, Ph.D.

Committee Member

Fr. Gerald Buonopane, Ph.D.

Keywords

flippase inhibitor, drug synergy, drug resistance, drug target, antimicrobial peptide, antifungal peptide

Abstract

Drug resistant microbes are a considerable challenge for modern medicine to overcome. The research described in this dissertation involved development of lipid flippase inhibitors and investigating their potential as antimicrobial agents against various drug resistant microbes. The microbes primarily investigated were methicillin resistant Staphylococcus aureus (MRSA) & Cryptococcus neoformans. Chapter 1 reviews the historical perspective and summarizes the current state of the field of research. In Chapter 2, the design space of an antimicrobial peptide known as humimycin was explored and the effects of modifications on its structure were observed against MRSA. Several key observations resulted. Most notably, the nanoparticles formed by the drug in solution are a likely contributor to the ability for various versions of the peptide to work synergistically when mixed in checkerboard assays. Chapter 3 details the investigation of a P₄ type ATPase flippase inhibitor as an antimicrobial agent against C. neoformans and to potentiate the effects of Caspofungin. Efficacy of the peptide was observed in vitro against the wild type strain. Annexin assays and confocal microscopy provide evidence towards the underlying mechanism of activity, relating to phosphatidylserine distribution in the membrane. Flippase inhibitors are drugs ripe for investigation due to their antimicrobial potential against drug resistant microbes.

Recommended Citation

Tancer, Robert, "Flippase Inhibitors as Antimicrobial Agents" (2022). Seton Hall University Dissertations and Theses (ETDs). 2981.
https://scholarship.shu.edu/dissertations/2981