Ian B. Seiple, PhD

Research in my group spans several disciplines including medicinal chemistry, microbiology, and structural biology. A central goal to our research is to identify major challenges in infectious diseases, especially in the treatment of resistant bacterial infections, and to develop new treatments by the strategic application of chemical synthesis. Our approaches are informed by structural binding data, known resistance pathways, and pharmacological considerations, requiring multidisciplinary research within the lab and strategic collaborations.

Modular Synthesis of Antibiotics

Co-evolution of microorganisms has resulted in an abundance of natural product small molecules that serve as effective weapons against pathogenic bacteria. This evolutionary process, however, does not often optimize drug-like properties for human use, and is inherently coupled with the evolution of resistance mechanisms. Our laboratory develops modular, fully synthetic routes to natural product scaffolds that we believe have not reached their potential. We are currently focusing on two classes of bacterial protein synthesis inhibitors: streptogramins (JACS 2017, Tetrahedron 2019) and lankacidins (Angewandte 2018, JACS 2020). These projects have led to a fruitful collaboration with the Fraser laboratory to investigate the molecular mechanisms of action of our antibiotic analogs in the bacterial ribosome with Cryo-EM (Nature 2020).

Expanding Antibiotic Spectra of Action

Of all of the effective antibiotics in our arsenal, less than half are effective against Gram-negative organisms. In a collaborative effort with the DeGrado and Craik laboratories, we are developing strategies to expand the spectra of activity of Gram-positive antibiotics to render them effective against Gram-negative pathogens, potentially doubling our pool of effective Gram-negative antibiotics. Our approach harnesses the reactivity of proteases in the bacterial periplasm to release Gram-positive payloads after they have penetrated the outer membrane.

Anticancer Targeted Protein Degradation

A joint student in the Seiple and Wells labs has initiated a project to harness the power of antibodies to achieve targeted protein degradation of oncogenic targets. We are pursuing two main strategies: 1) development of antibody-degrader conjugates, and 2) deveopment of bispecific antibody degraders of cell-surface proteins.

Discovery of New Antibiotics

In a new collaboration with the Rosenberg lab, our joint student is developing a mobile CRISPRi platform for the rapid, high-throughput screening of microbial extracts in search of new antibiotics. By employing double barcoding technology, we will be able to screen 96 compounds against 500 essential proteins in a single sequencing run.

Development of New Tools for Microscopy

In a fruitful collaboration with the Huang lab, we have developed trifunctional anchors for a new technique known as Expansion Microscopy (ExM). These anchors enable ExM to be performed with no fluorescense loss, which previously limited its potential. In combination with super-resolution strategies, we have achieved 5-nm resolution, 2-color images of the spatial distribution of nuclear lamina and histone markers. This is the highest resolution ever achieved with fluorescence microscopy.

Examining Imbalance in Chemistry Authorship
There is an enormous imbalance in gender representation in chemistry authorship. We have written a web scraper to statistically predict gender of authors in major chemistry journals. This provides up-to-date data on the underrepresentation of female authors in chemistry journals. We provide thoughts on how this can be improved in our first publications in this area.