Repurposing HDAC inhibitors to enhance ribonuclease 4 and 7 expression and reduce urinary tract infection.

Abstract

With the emergence of antibiotic-resistant bacteria, innovative approaches are needed for the treatment of urinary tract infections. Boosting antimicrobial peptide expression may provide an alternative to antibiotics. Here, we developed reporter cell lines and performed a high-throughput screen of clinically used drugs to identify compounds that boost ribonuclease 4 and 7 expression (RNase 4 and 7), peptides that have antimicrobial activity against antibiotic-resistant uropathogens. This screen identified histone deacetylase (HDAC) inhibitors as effective RNase 4 and RNase 7 inducers. Validation studies in primary human kidney and bladder cells confirmed pan-HDAC inhibitors as well as the HDAC class I inhibitor, MS-275, induce RNase 4 and RNase 7 to protect human kidney and bladder cells from uropathogenic Escherichia coli. When we administered MS-275 to mice, RNase 4 and 7 expression increased and mice were protected from acute transurethral E. coli challenge. In support of this mechanism, MS-275 treatment increased acetylated histone H3 binding to the RNASE4 and RNASE7 promoters. Overexpression and knockdown of HDAC class I proteins identified HDAC3 as a primary regulator of RNase 4 and 7. These results demonstrate the protective effects of enhancing RNase 4 and RNase 7, opening the door to repurposing medications as antibiotic conserving therapeutics for urinary tract infection.

• Authors: Laura Schwartz, M Skye Bochter, Aaron Simoni, Kristin Bender, Juan de Dios Ruiz Rosado, Israel Cotzomi-Ortega, Yuriko I Sanchez-Zamora, Brian Becknell, Sarah Linn, Birong Li, Nicholas Santoro, Tad Eichler, John David Spencer
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 120 Issue 4 Pg. e2213363120 (01 24 2023) ISSN: 1091-6490 [Electronic] United States
• PMID: 36652479 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• ribonuclease 4
• Ribonuclease 7
• entinostat
• Histone Deacetylase Inhibitors
• Ribonucleases
• Anti-Bacterial Agents

Topics

• Humans
• Mice
• Animals
• Histone Deacetylase Inhibitors (pharmacology)
• Escherichia coli (metabolism)
• Drug Repositioning
• Ribonucleases (metabolism)
• Urinary Tract Infections (drug therapy, microbiology)
• Anti-Bacterial Agents