(29h) A Nano-Enabled Anti-Antibiotic Biopolymer to Prevent Vancomycin Resistance in the Gastrointestinal Tract

Vancomycin (VAN) is a key antibiotic in the treatment of serious, life-threatening infections caused by Gram-positive bacteria that are unresponsive to other antibiotics. In clinical treatments, this cationic glycopeptide antibiotic is typically administered intravenously (IV) to patients and is largely excreted in urine. However, biliary excretion of a small fraction (~ 5-10%) of the administered dose leads to VAN bioavailability in the gastrointestinal (GI) tract that may result in microbiome dysbiosis and select for VAN-resistant bacteria. The unwanted VAN may drive the VAN-susceptible Enterococcus faecium (VSEfm), natural harmless colonizers in the GI, to resistant mutants. Given that developing new antibiotics for VAN-resistant bacteria may be extremely expensive and time consuming, we aim to break the connection between IV VAN administration and the emergence of antimicrobial resistance to protect VAN as a last-resort antibiotic. In this study, we engineered an anti-VAN biomaterial comprising a hairy cellulose nanocrystals (HCNC) and a Food and Drug Administration (FDA)-approved cholestyramine (CHA) resin to eliminate VAN from the GI tract. This orally administrable anti-VAN biomaterial, called AHCNC-CHA anti-antibiotic, had a high content of negatively charged carboxylate groups (~ 3 mmol g^-1). The VAN removal capacity of AHCNC-CHA was considerably high (~ 850 mg g^-1) and, at a dose of 20 mg mL^-1, it removed more than 95% of VAN (concentration = 1 mg mL^-1). Although VAN removal is controlled by electrostatic interactions, as confirmed in vitro via varying pH and ionic strengths, AHCNC-CHA remained efficient in the complex GI environment as a result of high charge density and partial VAN-selectively of dicarboxylate groups. Aligned with the in vitro findings, oral AHCNC-CHA treatment of subcutaneously VAN-injected mice effectively reduced the fecal shedding of VAN-resistant E. faecium by up to 63% and prevented the VAN resistance. We envision that this adjuvant therapy is translatable to humans to prevent the selection and spread of VAN-resistant pathogens, the main cause of nosocomial hospital-acquired infections in the modern healthcare systems.