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<p>Methicillin-resistant <i>Staphylococcus aureus</i> (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.</p>

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Candesartan cilexetil disrupts methicillin-resistant Staphylococcus aureus membrane and potentiates gentamicin and polymyxin B activity

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月15日

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  • Nagendran Tharmalingam,
  • Robert Wilson Kovacs,
  • Suelen Scarpa de Mello,
  • Philip Rupert Baldwin,
  • Harikrishna Sekar Jayanthan,
  • Kulandaisamy Arulsamy,
  • Rajmohan Rajmuthiah,
  • Fernanda Cristina Possamai Rossatto,
  • Katherine E. Manz,
  • Joseph A. DeGiorgis,
  • Orlando Acevedo,
  • Michael S. Gilmore,
  • Steven J. Ludtke,
  • Kurt D. Pennell,
  • Frederick M. Ausubel,
  • Eleftherios Mylonakis

摘要

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.