With the rise of antibiotic-resistant Staphylococcus aureus (S. aureus) strains (V/MRSA, i.e., Vancomycin/Methicillin-resistant bacteria), new mechanisms to target these infections are urgently needed. Monoclonal antibodies(mAbs)-based therapeutics such as AR-301 and 514G3 have shown success in treating S. aureus infections. Building on this, our lab is developing peptidoglycan (PG) probes that can be used to click onto viral-like nanoparticles (VLP), producing adjuvants that can activate memory B-cells and thus generate highly specific and selective mAbs. Initial data suggest that our mAbs, generated from small immunostimulatory PG fragment muramyl dipeptide (MDP), have significant potential for treating S. aureus infections in mice and exhibit a very specific binding profile to MDP-containing probes. Previous work and preliminary data suggest the linker plays an important role in adjuvant recognition by the adaptive immune response. Here, we showcase progress towards producing a suite of PG probes featuring different linker strategies around the glycopeptide. Moreover, we also aim to generate phosphate-containing PGs, which can be found in wall teichoic acid (WTAs) of S. aureus. This critical modification contributes to both the pathogenesis and proliferation of V/MRSAs. To obtain this phosphate modification, the human N-acetylglucosamine Kinase (NagK) was utilized to phosphorylate the PG monosaccharides. With these fragments in hand, immunological and binding assays can provide insights into the mechanism of how PGs interact with the human’s innate immune system. Further, generating robust mAbs from these fragments will ultimately lead to developing therapeutics against V/MRSAs.

M.G Finn

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