Colistin interactions with the mammalian urothelium

Area of Science:

• Urothelial physiology
• Epithelial barrier function
• Pharmacology of antibiotics

Background:

• Colistin is a critical antibiotic for treating multidrug-resistant Gram-negative infections.
• The urinary bladder epithelium (urothelium) forms a vital barrier against urinary tract pathogens and urine components.
• Understanding antibiotic effects on epithelial barriers is crucial for patient safety and treatment efficacy.

Purpose of the Study:

• To investigate the impact of colistin on the barrier integrity of the mammalian urinary bladder epithelium.
• To elucidate the mechanisms and conditions influencing colistin's effect on urothelial transepithelial conductance.
• To assess the reversibility and potential toxicity of colistin exposure to the urothelium.

Main Methods:

• Experiments were conducted on isolated rabbit urinary bladder epithelium (urothelium).
• Transepithelial conductance was measured following mucosal addition of colistin.
• Effects of varying membrane voltage, colistin concentration, and divalent cations were analyzed.
• Reversibility of conductance changes was assessed after short and long exposure times.

Main Results:

• Colistin significantly increased urothelial transepithelial conductance in a voltage-dependent manner.
• The increase in conductance was concentration-dependent, saturating at higher concentrations, suggesting membrane binding.
• Divalent cations reduced the colistin-induced conductance increase by competing for binding sites and blocking conductance.
• While short-term effects were reversible, prolonged colistin exposure resulted in partially irreversible changes, indicating potential toxicity.

Conclusions:

• Colistin alters the barrier function of the urinary bladder epithelium, primarily by increasing apical membrane conductance.
• The interaction is modulated by membrane potential and divalent cations, with potential for urothelial toxicity upon extended exposure.
• These findings highlight the importance of considering antibiotic effects on epithelial barriers during therapeutic use.