Mucin Binding Reduces Colistin Antimicrobial Activity

Abstract

Colistin has found increasing use in treating drug-resistant bacterial lung infections, but potential interactions with pulmonary biomolecules have not been investigated. We postulated that colistin, like aminoglycoside antibiotics, may bind to secretory mucin in sputum or epithelial mucin that lines airways, reducing free drug levels. To test this hypothesis, we measured binding of colistin and other antibiotics to porcine mucin, a family of densely glycosylated proteins used as a surrogate for human sputum and airway mucin. Antibiotics were incubated in dialysis tubing with or without mucin, and concentrations of unbound antibiotics able to penetrate the dialysis tubing were measured over time using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The percentage of antibiotic measured in the dialysate after 4 h in the presence of mucin, relative to the amount without mucin, was 15% for colistin, 16% for polymyxin B, 19% for tobramycin, 52% for ciprofloxacin, and 78% for daptomycin. Antibiotics with the strongest mucin binding had an overall polybasic positive charge, whereas those with comparatively little binding were less basic. When comparing MICs measured with or without added mucin, colistin and polymyxin B showed >100-fold increases in MICs for multiple Gram-negative bacteria. Preclinical evaluation of mucin binding should become a standard procedure when considering the potential pulmonary use of new or existing antibiotics, particularly those with a polybasic overall charge. In the airways, mucin binding may reduce the antibacterial efficacy of inhaled or intravenously administered colistin, and the presence of sub-MIC effective antibiotic concentrations could result in the development of antibiotic resistance.

A Low-Molecular-Weight Alginate Oligosaccharide Disrupts Pseudomonal Microcolony Formation and Enhances Antibiotic Effectiveness

“…Colistin acts through positively charged electrostatic interactions with the negatively charged bacterial lipopolysaccharide (LPS), facilitating membrane disruption. The observed lowering of the efficacy of colistin in AS medium, therefore, may not only be related to an altered growth rate in this environment (which mimics growth conditions in the CF lung), but also may be due to LPS modification and/or direct binding by mucin in the AS medium, effectively sequestering free antibiotic (41). This EPS effect, and the apparent differences in MICs for colistin-treated NH57388A (with MIC values 4 times greater in AS than in MH medium) reflect the 10 4 -fold difference previously observed between MIC (0.094 g/ml) and MBEC (Ͼ512 g/ml) values for NH57388A in vitro (32).…”

Pharmacokinetics/Pharmacodynamics of Pulmonary Delivery of Colistin against Pseudomonas aeruginosa in a Mouse Lung Infection Model

“…Since the observed ELF concentrations in the current study after inhalation were Ͼ64ϫ MIC, the interaction between colistin and pulmonary surfactant was assumed to be negligible. On the contrary, following intravenous administration, colistin exposure in the ELF was minimal, and below 2.21 mg/liter (limit of quantification [LOQ]), the inhibitory effect of pulmonary surfactant is dramatic and should be considered (32).…”

Substantial Targeting Advantage Achieved by Pulmonary Administration of Colistin Methanesulfonate in a Large-Animal Model

“…3B), whereas CMS may be more restricted to the ELF along with colistin immediately after its formation. Furthermore, colistin has been shown to bind strongly to mucin in lung fluids, thus limiting its antimicrobial activity (47).…”