Ion exchange biomaterials to capture daptomycin and prevent resistance evolution in off-target bacterial populations

Abstract

Daptomycin (DAP), a cyclic anionic lipopeptide antibiotic, is among the last resorts to treat multidrug resistant (vancomycin resistant Enterococcus faecium or methicillin resistant Staphylococcus aureus) Gram-positive bacterial infections. DAP is administered intravenously and biliary excretion results in the introduction of DAP ([~]5-10 % of the intravenous DAP dose) arriving in the gastrointestinal (GI) tract where it drives resistance evolution in off-target populations of Enterococcus faecium bacteria. Previously, we have shown that the oral administration of cholestyramine, an ion exchange biomaterial (IXB) sorbent, prevents DAP treatment from enriching DAP-resistance in populations of E. faecium shed from mice. Here, we engineer the biomaterial-DAP interfacial interactions to uncover the antibiotic removal mechanisms. The IXB-mediated DAP capture from aqueous media was measured in both controlled pH/electrolyte solutions and in simulated intestinal fluid (SIF) to uncover the molecular and colloidal mechanisms of DAP removal from the GI tract. Our findings show that the IXB electrostatically adsorbs the anionic antibiotic via a time-dependent diffusion-controlled process. Unsteady-state diffusion-adsorption mass balance describes the dynamics of adsorption well, and the maximum removal capacity is beyond the electric charge stoichiometric ratio because of DAP self-assembly. This study may open new opportunities for optimizing cholestyramine adjuvant therapy to prevent DAP resistance, as well as designing novel biomaterials to remove off-target antibiotics from the GI tract. TOC O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=137 SRC="FIGDIR/small/495716v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@ec034eorg.highwire.dtl.DTLVardef@cd1106org.highwire.dtl.DTLVardef@118dbcborg.highwire.dtl.DTLVardef@106287c_HPS_FORMAT_FIGEXP M_FIG C_FIG