A promising approach in combatting infections from antibiotic resistant bacteria/fungi is using therapeutic monoclonal antibodies (mAbs) that can bind the outer surfaces of microbes. We have developed a synthetic vaccine platform that can rapidly generate mAbs against surface glycans from desired strains, such as lipopolysaccharides and capsular polysaccharides. To create therapeutic antibodies against Ruminococcus gnavus, Burkholderia multivorans, and Staphylococcus aureus, we synthesize glycan antigens from each strain that are necessary for use in our glycoconjugate vaccine platform. Blooms of the Gram-positive bacterium Ruminococcus gnavus have been correlated with inflammatory bowel disease, and recently a polysaccharide produced by this organism was shown to stimulate release of inflammatory cytokines. This stimulation was proposed to signal through toll-like receptor 4. We have synthesized the pentasaccharide repeating unit of this polysaccharide and showed that it stimulates TNF-α and IL-6 release from bone marrow-derived dendritic cells in a TLR4-dependent manner. A related glycan does not stimulate significant cytokine release, demonstrating TLR4 selectivity in glycan recognition. Ceragenins are a class of antimicrobials that have broad-spectrum activity against many antimicrobial resistant strains of fungi, Gram-negative bacteria, and Gram-positive bacteria. Previous work has shown that ceragenins can tolerate large structural modifications without loss of activity, such as incorporation of long polyethylene glycol linkers and other domains with selective binding activities. Here we perform structure activity relationship studies of the tail domain of ceragenins to bind hydroxyapatite to combat bone infection, copper for preventing implant related infections, and as a bioresorbable antimicrobial for use in bioresorbable medical devices.

Antimicrobial peptides (AMPs) are ubiquitous and display broad-spectrum antimicrobial activity that can control bacterial colonization of surfaces. Ceragenins are small-molecule mimics of AMPs and have several advantages over AMPs, including cost of manufacture and stability. A ceragenin, CSA-120, modified with an acrylamide group was directly incorporated into fluoropolymer coatings as a means of inhibiting bacterial biofilm formation. The ceragenin-containing coatings displayed improved performance. By conjugating a copper chelating group to the ceragenin, chelation of 64Cu by the conjugate was effective and provided a stable complex that allowed in vivo imaging. This conjugate may provide a means of identifying infection sites in patients presenting general signs of infection without localized symptoms. A combination nanoparticle comprised of a maghemite core for enhanced T2 MRI contrast diagnostics, a colloidal silver shell acting as an antimicrobial and therapeutic vehicle, and a ceragenin (CSA- 124) surfactant providing microbial adhesion was synthesized and characterized by multiple methods. Silver nanoparticles conjugated with ceragenin, CSA-124, as a potential Gram-positiveselective antimicrobial were synthesized and termed as CSA-SNPs. Herein, CSA-SNPs are characterized using multiple methods and the antimicrobial properties are determined through minimum inhibitory concentration/minimum bactericidal concentration (MIC/MBC) and time-kill study. Prostanoids are a natural subclass of eicosanoids generated mainly from metabolic oxidation of arachidonic acid. Cyclopentenone prostaglandins (cyPGs) contain a highly reactive α,β-unsaturated carbonyl group in their cyclopentenone ring and possess three main potentially therapeutic properties: anti-inflammatory, antiproliferative and antiviral. We designed and synthesized EC and its derivatives in reducing secretion of pro-inflammatory cytokines IL-6 and IL-12. Mucosal-Associated Invariant T (MAIT) Cells are unique innate-like T cells and play a key role in host defense against bacterial and fungal infection as well as in human autoimmune diseases. The MAIT cells are activated through T-cell receptor αβ chain (TCR-αβ) binding with the MR1-ligand, which is vitamin B metabolites presented on MR1. Rribityllumazines, one of important MR1-ligand was synthesized in my study.

Hospital-acquired infections (HAIs) pose a significant and increasing threat to global health. One primary cause of this threat is increasing antibiotic resistance. As traditional antibiotics continue to grow less effective, there is an urgent need for novel antimicrobial strategies. This work explores the potential of ceragenins, also known as cationic steroid antimicrobials (CSAs), as a promising alternative to combat HAIs. Specifically, we investigated potential roles that CSAs can play in the context of multiple medical device coatings in healthcare settings. Ceragenins are synthetic mimic of antimicrobial peptides (AMPs) which exhibit broad-spectrum antimicrobial activity against many common pathogens that have been cited as high priority by global health organizations. Unlike traditional antibiotics, which rely on specificity to bacterial enzymes or processes, ceragenins disrupt microbial membranes generally. This mechanism of action allows ceragenins to bypass many of the related antibiotic resistance mutations of bacteria and fungi. As microbial membranes are a highly conserved and fundamental structure of these pathogens, it is much more difficult for microbes to develop mutations that prevent CSA binding. Additionally, ceragenins are resistant to both host and pathogenic proteolytic degradation and are cost-effective to produce, which place CSAs as an attractive alternative to traditional antibiotics. This research investigates the integration of ceragenins into various medical devices to prevent HAIs. Specifically, we investigated silicone tissue expanders, peripherally inserted central catheter (PICC) lines, and adhesive devices which include both polyacrylate and silicone scar tape. These studies include the development of coating techniques to maximize appropriate antimicrobial activity while maintaining stability and biocompatibility across these different base materials. Our experimental results demonstrate that ceragenin-coated devices significantly reduce microbial colonization and biofilm formation. We considered the length of antimicrobial activity needed and developed coatings that would be appropriate for those use cases. This reduction in harmful pathogenic colonization demonstrates their potential to improve patient outcomes and reduce healthcare costs associated with HAIs. Further research and development could facilitate the continued adoption of ceragenin-based coatings in medical devices, which can reduce the incidence of HAIs while contributing to the broader fight against antibiotic-resistant infections worldwide.