All ETDs from UAB

Advisory Committee Chair

Olaf Kutsch

Advisory Committee Members

Susan Birket

Juan Calix

Terje Dokland

Michael Gray

Document Type

Dissertation

Date of Award

2022

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) is a serious human pathogen with a staggering potential for multi-drug resistance. Because of this, the Centers for Disease Control and Prevention and the World Health Organization monitor the spread of MRSA and encourage antibiotic development efforts targeting this pathogen. Despite this, few antibiotics have been developed and brought to market in recent decades. To continue treating infections caused by this organism, we must identify novel antibiotic molecules with different mechanisms of action from known antibiotics. Bacterial copper-dependent inhibitors (CDIs), molecules that become antibacterial in the presence of copper (Cu), have been studied as a novel class of antibiotics. However, CDIs are notoriously toxic due to the inherent and self-potentiating toxicity of Cu itself. Recently, zinc (Zn), though previously understood to be an essential micronutrient, can become antibacterial under certain conditions, but unlike Cu, Zn does not redox cycle and produce reactive oxygen species of its own accord. Based on this, we sought to activate antibacterial action in small molecules with Zn rather than Cu in the following studies. In the first study, we demonstrate Zn-activated antibiotics are readily identifiable in characterized chemical space against MRSA using a Zn-dependent screening approach, and we characterize the most promising of these hits, the sunscreen ingredient avobenzone (AVB), as an anti-staphylococcal Zn-activated metallo-antibiotic. In the second study, we expand upon Zn-activated metallo-antibiotics by exploring the metal specificity of metal-binding and antibacterial classes of privileged structures to show Zn-dependent antibiotics, like other drugs, can be optimized for a specific activity with a structure activity relationship study (SAR). Here we demonstrate metal specificity of 8-hydroxyquinolines and benzimidazoles is dependent on specific R-group modifications. Ultimately, our data establish Zn-dependent antibiotics as their own class of antibiotics with potential for development pipeline that mirrors those already in use for antibiotic development.

Available for download on Thursday, May 09, 2024

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