Sucheck Chemistry Group

Program 1. Targeting Mycobacterial Cell-Envelope Biosynthesis, Trehalose Pathways, and Persistence

Our research targets vulnerable pathways in mycobacteria, with a particular emphasis on cell-envelope biosynthesis, trehalose metabolism, and mechanisms that support persistence in Mycobacterium tuberculosis. We use synthetic carbohydrates, glycomimetics, and small-molecule design to create mechanistic probes and inhibitor leads for enzymes involved in mycobacterial growth, virulence, and survival.

A major focus of this work has been the study of trehalose- and mycolic acid-related pathways. Our publications include inhibitor and structural studies on the Antigen 85 complex, especially Ag85C, which transfers mycolic acids from trehalose monomycolate during cell-wall assembly; GlgE, a maltosyltransferase involved in α-glucan biosynthesis whose disruption causes toxic maltose-1-phosphate accumulation; and OtsB2, the trehalose-6-phosphate phosphatase in the OtsA/OtsB pathway. Across these targets, we have developed substrate-inspired analogues, glycoconjugates, covalent and noncovalent inhibitors, and structure-guided probe molecules to better define enzyme recognition and inhibition.

More recently, our work has expanded strongly into Pks13, an essential enzyme in mycolic acid biosynthesis. Published studies from the group include discovery of benzoxazole-based Pks13 inhibitors with on-target activity, inhibition of mycolic acid synthesis, and low to no cytotoxicity in tested scaffolds, as well as trehalose–Pks13 inhibitor conjugates designed to improve antimycobacterial potency or selectivity by exploiting mycobacterial carbohydrate uptake and cell-envelope biology.

In parallel, we have developed marine natural product-inspired meroterpenoids related to (+)-puupehenone that show activity against dormant M. tuberculosis, helping extend the program beyond essential enzymes to persistence-focused antitubercular discovery. Related derivatives also showed activity against Clostridioides difficile, with several compounds reducing exotoxin production, highlighting broader anti-infective potential for this chemistry.

Program 2. Synthetic Glycoconjugate Vaccines and Oligosaccharide-Based Immunotherapeutics

Carbohydrates found in bacterial and tumor-associated glycoconjugates often serve as highly specific molecular signatures, making them attractive targets for vaccine and immunotherapeutic development. Our research focuses on the synthesis of structurally defined oligosaccharides and glycoconjugates that can be used to probe immune recognition and serve as components of fully synthetic or semisynthetic vaccine platforms.

A major area of emphasis is the development of glycoconjugate vaccines targeting Pseudomonas aeruginosa, an important ESKAPE pathogen. In addition to earlier work on L-rhamnose-containing oligosaccharide epitopes from the outer core region of P. aeruginosa lipopolysaccharide, our more recent studies have expanded to the synthesis of defined fragments of the P. aeruginosa exopolysaccharide Psl. These synthetic oligosaccharides have been functionalized for chemoselective conjugation to carrier proteins such as CRM197 and evaluated in modern adjuvant formulations, including QS-21/Pam3CSK4 liposomal systems, to assess antigenicity and functional immune responses.

We are also developing strategies to enhance vaccine immunogenicity by leveraging endogenous human anti-L-rhamnose antibodies. Our published studies showed that rhamnose-containing constructs can recruit these natural antibodies and improve targeting to antigen-presenting cells, providing a complementary platform for boosting immune responses in vaccine design. Together, these efforts combine synthetic carbohydrate chemistry, glycoconjugate assembly, and immune-focused formulation to advance new vaccines and immunotherapeutic agents for infectious disease and cancer.