Browsing by Subject "natural products"

Natural products belonging to the lipid II-binding family act as potent antimicrobial agents by disrupting cell wall biosynthesis via sequestering the late-stage intermediate lipid II. However, the emergence of resistance mechanisms and poor bioavailability have hindered the utility of these molecules as promising therapeutic intervention strategies to combat pathogenic bacterial infections. Gaining a deeper understanding of structural components and biosynthetic pathways can lead to the creation of second-generation derivatives to improve bioactivity and pharmacological properties. To explore this superfamily, we have used bioanalytical, biochemical, synthetic, computational, and enzymatic approaches that have been applied to three distinct projects. The first includes efforts to characterize the relationship between structural feature and bioactivity for the lipid II-binding CDA (calcium dependent antibiotic), malacidin. Through a series of minimally complex analogs, we determined non-proteinogenic amino acids and the N-acyl fatty acid moiety are essential for bioactivity. For the second project, we investigated a conserved mechanism of action for phylogenetically-related natural products within the lasso peptide subfamily. This work led to the discovery of a novel class I lasso peptide, arcumycin, and we validated a conserved mechanism of action for Actinobacteria-produced lasso peptides in targeting lipid II biosynthesis. Our last project sought to elucidate the mechanism of lipoinitiation for the ramoplanin family of molecules. Through a series of bioactivity assays, we found the transfer to the acyl carrier protein (ACP) in a fatty acyl-AMP ligase (FAAL)-dependent manner determined the specificity of lipids selected in the biosynthetic process. Collectively, through each project we have gained a deeper understanding of the structural elements and biosynthetic pathways of lipid II-binding antimicrobials.

Across the tree of life, specialized metabolites mediate ecological interactions and can ultimately drive evolution. Characterization of these small molecules have led scientists to a greater comprehension of ecological niches at the macro- and micro-scale. A group of medicinally important organisms with life cycles that include various ecological niches are apicomplexan parasites. The most notorious parasites belong to the genera Plasmodium and Toxoplasma, which are responsible for malaria and toxoplasmosis, respectively. Traditional efforts to reduce malaria include pharmaceuticals and prevention of mosquito-based transmission through insecticides and bed nets. Despite this, malaria has prevailed. Efforts were devised to understand the chemical ecology surrounding malaria parasites during the mosquito stage to ultimately reduce transmission. Through structure-, bioinformatic-, and coculture-guided approaches, we have uncovered chemical space within the mosquito-microbiome and evaluated how microbial-produced small molecules influence the parasite during its vector stage. We have also expanded our knowledge of parasite-produce specialized metabolites. Within Toxoplasma parasites, we have begun to characterize a polyketide synthase (PKS) with unknown resultant products. Together, this work provides the basis for understanding how specialized metabolites within the mosquito microbiome affect the Plasmodium parasite transmission capacity while also investigating an underexplored area of natural product chemistry within Toxoplasma parasites.