Peter Smith
pasmith@scripps.edu

B.S. in Biology and Chemistry, 2004,
Purdue University Research with Prof. Alan Friedman

Honors:
— Best Biology Oral Research Presentation, TSRI Graduate Symposium 2008
— Honorable Mention: National Science Foundation Graduate Research Fellowship 2005
— Howard Hughes Undergraduate Summer Research Fellowship Summer 2003
— Rizuka Summer Research Fellowship Summer 2002
— Howard Hughes Undergraduate Summer Research Fellowship Summer 2001
— Phi Beta Kappa Honors Society 2003

Mentor:
Professor Floyd Romesberg
Department of Chemistry

Research at TSRI:
The majority of antibiotics currently in use are natural products co-opted from natural microbial arms races. The widespread use of these compounds has revolutionized the treatment of infectious disease, but such use also provides a relentless selection pressure for the evolution of resistance, necessitating the continual development of new antibiotics. Unfortunately, identification of novel natural product antibiotics has become increasingly difficult, so chemists have instead focused (rather successfully) on re-engineering known antibiotics to overcome resistance. Such efforts, however, are limited by the number of known antibiotic scaffolds. I hypothesize that much like the modern era’s arms race between medicinal chemists and bacteria, it is possible, perhaps even likely, that the natural arms races have been punctuated by cycles of antibiotic activity and inactivity mediated by the co-evolution of antibiotics and their targets. Molecules that evolved as antibiotics but are currently inactive due to the natural evolution of resistance are unlikely to be identified by traditional drug discovery efforts. However, these molecules could provide much needed scaffolds for the next generation therapies.

One potential “lost antibiotic” is Arylomycin A2, a bacterial Signal Peptidase inhibitor that displays activity against a few obscure soil bacteria but is ineffective against almost all human pathogens. By studying the evolution of resistance in the few species of bacterial that are Arylomycin A2 sensitive, I have discovered a critical and previously unappreciated allele within Signal Peptidase that confers high level resistance to this antibiotic. Using genetics, biochemistry, and phylogenetics, I am studying the mechanism by which this allele confers resistance and how widespread this mechanism is in nature. My studies indicate that Arylomycin A2 was once a broad spectrum agent and imposed a significant selective pressure in the evolution of the Signal Peptidase binding pocket. Furthermore, knowledge of how resistance to Arylomycin A2 emerged in nature suggests modifications that could restore this broad spectrum activity. More importantly, if these results are generalizable, they suggest that discovery and re-engineering of “lost antibiotics” could provide the foundation for future generations of antimicrobial therapies. Investigations as to the generality of this model are currently underway.

Publications:
“Relics of the Microbial Arms Race: A Source for Novel Antibiotics” Smith P., Roberts T., Romesberg F. (manuscript in preparation)

“SOS Regulatory Elements are Essential for UPEC Pathogenesis” Li B., Smith P., Horvath D, Romesberg F., Justice S. (manuscript in preparation)

“Combating bacteria and drug resistance by inhibiting mechanisms of persistence and adaptation” Smith P., Romesberg F. Nat. Chem. Bio., 2007, 3, 549-556.

“Structural and Initial Biological Analysis of Synthetic Arylomycin A2” Roberts T., Smith P., Cirz R., Romesberg F. J. Am. Chem. Soc., 2007, 129, 15830-15838.