New chemistry and new discoveries! 

Our research program is inspired by the challenge and importance of elucidating chemical structure and function in complex biological systems. We have introduced uniquely enabling problem-solving approaches using solid-state NMR spectroscopy to determine atomic- and molecular-level detail in complex macromolecular assemblies and intact cells and biofilms. We also leverage our expertise in biochemistry, microbiology, and drug discovery to uncover new chemistry underlying outstanding biological processes and to identify strategies to treat human diseases. We have launched a collaborative antibacterial drug design program integrating synthesis, chemical biology, and mechanistic biochemistry and biophysics directed at the discovery and development of new antibacterial therapeutics targeting difficult-to-treat bacteria. 

We recently identified a new chemical structure never before observed in nature: phosphoethanolamine cellulose. This discovery emerged from new protocol development and new strategies using solid-state NMR to examine bacterial biofilms coupled with electron microscopy and biochemical analysis. We are investigating bacterial biofilms that include pEtN cellulose as well as fascinating extracellular functional amyloid fibers termed curli and other matrix components. We strive to understand at a molecular and atomic level how cells self-assemble fascinating extracellular structures and how bacteria use these building blocks to construct organized biofilm architectures. We are also engaged in identifying small molecules to interfere with these processes and in understanding the modes of action of newly discovered antibacterials and anti-virulence compounds.
 
Bacterial Biofilms & Cell Walls

Bacteria occupy remarkably distinct niches on our planet and the propensity for bacteria to associate with surfaces and with each other in nearly all ecosystems far exceeds the tendency to persist in suspension, living freely in a planktonic state. Bacteria are found attached to rocks and soil particles, corals and ocean sponges. Bacteria symbiotically colonize plants and humans as well as fish and squid, resulting in mutual benefit to both microbe and host. Pathogenic and unwelcome bacteria colonize host tissues, leading to cellular injury and disease. Specific adhesion strategies have evolved in order to facilitate bacterial attachment. Understanding the molecular mechanisms and functional implications of microbial adhesion is crucial to generating complete descriptions of our ecosystems and attempting to control and prevent the unfortunate and often devastating consequences of infectious diseases.

Bacterial adhesion is an initial and crucial event in the process of biofilm formation. Biofilms are complex, organized bacterial assemblies that exhibit reduced sensitivity to conventional antibiotics, host defenses, and external stresses. Biofilms within the host are implicated in serious and persistent infectious diseases including cystic fibrosis, chronic otitis media, and urinary tract infection. In the environment, biofilms can serve as reservoirs for pathogens and are associated with biofouling.

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Antibacterial Drug Discovery

New antibiotics and anti-infective strategies are needed as bacteria emerge resistant and tolerant to “drugs of last resort.” We are introducing new antibacterial compounds, inspired by the challenge and vision of breaching Gram-positive cell walls and Gram-negative outer membranes to kill both actively growing cells and slow-growing biofilm-associated bacteria and persister cells. 

Our preliminary studies have now led to the identification of agents that significantly outperform vancomycin, that are comparable or better than current clinically used agents in preliminary comparisons, that exhibit behavior consistent with a new mode of action or dual modes of action, and that provide the structural and conceptual basis for what could be a broadly applicable strategy for generating new antibiotics based on facile synthetic modification of existing antibiotics. 

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V-r8_JACS2018_TOC

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Rifapentine

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Microbial Amyloids & Polysaccharides

New antibiotics and anti-infective strategies are needed as common pathogens such as S. aureus, E. coli and Streptococcus species emerge resistant and tolerant to “drugs of last resort.” We are introducing new antibacterial compounds, inspired by the challenge and vision of breaching Gram-positive cell walls and Gram-negative outer membranes to kill both actively growing cells and slow-growing biofilm-associated bacteria and persister cells. 

Our preliminary studies have now led to the identification of agents that significantly outperform vancomycin, that are comparable or better than current clinically used agents in preliminary comparisons, that exhibit behavior consistent with a new mode of action or dual modes of action, and that provide the structural and conceptual basis for what could be a broadly applicable strategy for generating new antibiotics based on facile synthetic modification of existing antibiotics. 

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Macromolecular and whole-cell NMR 

Solid-state NMR is a prominent technique in our toolbox. It is well suited to provide compositional and atomic-level insights into complex heterogeneous systems such as intact plant leaves and bacterial biofilms that pose a challenge to analysis by traditional methods. The use of solid-state NMR spectroscopy to dissect macrosystems is powerful, versatile, and broadly applicable to diverse systems, but there are no set protocols. We are developing protocols to introduce stable isotope labels selectively in vivo in bacteria, plants, and cellular systems, often manipulating biosynthetic pathways to take up labeled components such as amino acids, carbohydrates, or metabolites. We track these labels by various solid-state NMR detection schemes to understand how they are incorporated or transformed. The selection and development of pulsed NMR schemes depends on the problem that needs to be solved. Our goals are not typically ones to determine total structures, but rather to connect partial local structure with biological function to solve a wide number of outstanding problems and to understand the fundamental chemistry of biological systems.

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