d‑Amino Acid Mediated Recruitment of Endogenous Antibodies to Bacterial Surfaces

The number of antibiotic resistant bacterial strains has been continuously increasing over the last few decades. Nontraditional routes to combat bacteria may offer an attractive alternative to the ongoing problem of drug discovery in this field. Herein, we describe the initial framework toward the development of bacterial d-amino acid antibody recruitment therapy (DART). DART represents a promising antibiotic strategy by exploiting the promiscuity of bacteria to incorporate unnatural d-amino acids and subsequently recruit antibodies to the bacterial surface. The conjugation of 2,4-dinitrophenyl (DNP) to various d-amino acids led to the discovery of a d-amino acid that specifically tags the surface of <i>Bacillus subtilis</i> and <i>Staphylococcus aureus</i> for the recruitment of anti-DNP antibodies (a highly abundant antibody in human serum). This system represents a novel strategy as an antibacterial therapy that targets planktonic Gram-positive bacteria

Dipeptide-Based Metabolic Labeling of Bacterial Cells for Endogenous Antibody Recruitment

The number of antibiotic-resistant bacterial infections has increased dramatically over the past decade. To combat these pathogens, novel antimicrobial strategies must be explored and developed. We previously reported a strategy based on hapten-modified cell wall analogues to induce recruitment of endogenous antibodies to bacterial cell surfaces. Cell surface remodeling using unnatural single d-amino acid cell wall analogues led to modification at the C-terminus of the peptidoglycan stem peptide. During peptidoglycan processing, installed hapten-displaying amino acids can be subsequently removed by cell wall enzymes. Herein, we disclose a two-step dipeptide peptidoglycan remodeling strategy aimed at introducing haptens at an alternative site within the stem peptide to improve retention and diminish removal by cell wall enzymes. Through this redesigned strategy, we determined size constraints of peptidoglycan remodeling and applied these constraints to attain hapten–linker conjugates that produced high levels of antibody recruitment to bacterial cell surfaces

Identification of a Potent, Selective, and Efficacious Phosphatidylinositol 3‑Kinase δ (PI3Kδ) Inhibitor for the Treatment of Immunological Disorders

PI3Kδ plays an important role controlling immune cell function and has therefore been identified as a potential target for the treatment of immunological disorders. This article highlights our work toward the identification of a potent, selective, and efficacious PI3Kδ inhibitor. Through careful SAR, the successful replacement of a polar pyrazole group by a simple chloro or trifluoromethyl group led to improved Caco-2 permeability, reduced Caco-2 efflux, reduced hERG PC activity, and increased selectivity profile while maintaining potency in the CD69 hWB assay. The optimization of the aryl substitution then identified a 4′-CN group that improved the human/rodent correlation in microsomal metabolic stability. Our lead molecule is very potent in PK/PD assays and highly efficacious in a mouse collagen-induced arthritis model