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.