A Dual-Mechanism Antibiotic Kills Gram-Negative Bacteria and Avoids Drug Resistance.

TitleA Dual-Mechanism Antibiotic Kills Gram-Negative Bacteria and Avoids Drug Resistance.
Publication TypeJournal Article
Year of Publication2020
AuthorsMartin, JK, Sheehan, JP, Bratton, BP, Moore, GM, Mateus, A, Li, SHsin-Jung, Kim, H, Rabinowitz, JD, Typas, A, Savitski, MM, Wilson, MZ, Gitai, Z
JournalCell
Volume181
Issue7
Pagination1518-1532.e14
Date Published2020 Jun 25
ISSN1097-4172
Abstract

The rise of antibiotic resistance and declining discovery of new antibiotics has created a global health crisis. Of particular concern, no new antibiotic classes have been approved for treating Gram-negative pathogens in decades. Here, we characterize a compound, SCH-79797, that kills both Gram-negative and Gram-positive bacteria through a unique dual-targeting mechanism of action (MoA) with undetectably low resistance frequencies. To characterize its MoA, we combined quantitative imaging, proteomic, genetic, metabolomic, and cell-based assays. This pipeline demonstrates that SCH-79797 has two independent cellular targets, folate metabolism and bacterial membrane integrity, and outperforms combination treatments in killing methicillin-resistant Staphylococcus aureus (MRSA) persisters. Building on the molecular core of SCH-79797, we developed a derivative, Irresistin-16, with increased potency and showed its efficacy against Neisseria gonorrhoeae in a mouse vaginal infection model. This promising antibiotic lead suggests that combining multiple MoAs onto a single chemical scaffold may be an underappreciated approach to targeting challenging bacterial pathogens.

DOI10.1016/j.cell.2020.05.005
Alternate JournalCell
PubMed ID32497502
Grant ListT32 GM007388 / GM / NIGMS NIH HHS / United States