A Small-Molecule Modulator of Metal Homeostasis in Gram-Positive Pathogens
Abstract
Staphylococcus aureus is a leading agent of antibiotic-resistant bacterial infections in the world. S. aureus tightly controls metal homeostasis during infection, and disruption of metal uptake systems impairs staphylococcal virulence. We identified small molecules that interfere with metal handling in S. aureus to develop chemical probes to investigate metallobiology in this organism. Compound VU0026921 was identified as a small molecule that kills S. aureus both aerobically and anaerobically. The activity of VU0026921 is modulated by metal supplementation, is enhanced by genetic inactivation of Mn homeostasis genes, and correlates with increased cellular reactive oxygen species. Treatment with VU0026921 causes accumulation of multiple metals within S. aureus cells and concomitant upregulation of genes involved in metal detoxification. This work defines a small-molecule probe for further defining the role of metal toxicity in S. aureus and validates future antibiotic development targeting metal toxicity pathways.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Oct 27, 2020
- Source ID
- 10.1128/mbio.02555-20
Entities
People
- Aaron B. Bowman
- Andy Weiss
- Daisy Unsihuay
- Eric P. Skaar
- Gary A. Sulikowski
- Gleb Pishchany
- Hassan Al-tameemi
- Jeffrey M Boyd
- Kwangho Kim
- Kyle J. Horning
- Lillian J. Juttukonda
- William N. Beavers
Organizations
- American Heart Association
- Harvard Medical School
- National Institute of Allergy and Infectious Diseases
- National Institute of Environmental Health Sciences
- National Institute of General Medical Sciences
- National Science Foundation
- Rutgers University
- United States Department of Agriculture
- Vanderbilt University