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 have not reached their potential. This allows us to interrogate structure–function relationships, access new molecules that overcome resistance, and occasionally even correct erroneous structural assignments.

Representative publications:

Modular, scalable synthesis of group A streptogramin antibiotics (JACS 2017)

Modular Approaches to Lankacidin Antibiotics (JACS 2020)

Synthesis of group A streptogramins that overcome Vat resistance (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.

Representative publications:

Platform to Discover Protease-Activated Antibiotics and Application to Siderophore-Antibiotic Conjugates (JACS 2020)

Development of New Tools to Study Biological Systems

We apply our skills in chemistry to develop new tools that can be used to study biological systems. In collaboration with the Wang lab at UCSF, we have developed photoactivatable crosslinkers to study protein–protein interactions in an incredibly practical way. In a fruitful collaboration with the Huang lab at UCSF, 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.

Representative Publications:

Photocaged Quinone Methide Cross-linkers for Light-controlled Chemical Cross-linking of Protein-protein and Protein-DNA Complexes (ACIE 2019)

Label-retention expansion microscopy (BioRXiv 2019)

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, which provides data on the underrepresentation of female authors in chemistry journals. We provide thoughts on how this can be improved in our first publication in this area.

Representative Publications:

Examining Gender Imbalance in Chemistry Authorship (ACS Chem. Bio. 2020)