Candesartan cilexetil disrupts methicillin-resistant Staphylococcus aureus membrane and potentiates gentamicin and polymyxin B activity
Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of bacterial infections, but treatment options are limited due to MRSA multi-drug resistance. The anti-hypertensive drug Candesartan cilexetil (CC) exhibits potent anti-MRSA activity. It permeabilizes the membrane of MRSA cells and potentiates the activity of aminoglycoside antibiotics. Here, we used a variety of methods to elucidate the mechanism by which CC disrupts membrane homeostasis. We show that CC binds to bilayer lipid molecules, decreases membrane fluidity, down-regulates cell membrane and cell wall related genes and related metabolites, and decreases C20 fatty acids (C20:0). Decreasing C20:0 fatty acids confers CC- resistance, which can be reversed by C20:0 supplementation. Structural activity relationship analysis shows that the tetrazole ring and ester carbonic acid of CC are critical for antibacterial activity. Finally, CC reduces MRSA-MW2 replication in a murine MRSA abscess model, supporting a potential role of CC as a lead antimicrobial compound/potentiator against MRSA.
Authors
- Steven J. Ludtke (ORCID: https://orcid.org/0000-0002-1903-1574)
- Nagendran Tharmalingam (ORCID: https://orcid.org/0000-0001-6107-3754)
- Michael S. Gilmore (ORCID: https://orcid.org/0000-0001-6389-832X)
- Katherine E. Manz (ORCID: https://orcid.org/0000-0002-8225-9168)
- Suelen Scarpa de Mello (ORCID: https://orcid.org/0000-0001-6389-6041)
- Rajmohan Rajmuthiah
- Fernanda Cristina Possamai Rossatto (ORCID: https://orcid.org/0000-0003-1875-2377)
- Joseph A. DeGiorgis
- Harikrishna Sekar Jayanthan
- Frederick M. Ausubel (ORCID: https://orcid.org/0000-0002-6927-8460)
- Orlando Acevedo
- Kulandaisamy Arulsamy
- Robert Wilson Kovacs
- Philip Rupert Baldwin
- Eleftherios Mylonakis
- Kurt D. Pennell
Institutions
- Massachusetts Eye and Ear Infirmary (US)
- Boston Children's Hospital (US)
- Houston Methodist (US)
- Harvard University (US)
- University of Miami (US)
- Baylor College of Medicine (US)
- Providence College (US)
- Vanderbilt University (US)
- Cornell University (US)
- Brown University (US)
- Rhode Island Hospital (US)
- Massachusetts General Hospital (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-03-15
- DOI
- https://doi.org/10.1038/s41467-026-70173-0
- Primary Topic
- Antimicrobial Resistance in Staphylococcus
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Science Foundation
- Cancer Prevention and Research Institute of Texas
- Brown University
- National Institutes of Health
- Division of Chemical, Bioengineering, Environmental, and Transport Systems