Doctor of Philosophy, Stanford University, CHEM-PHD (2012)
Bachelor of Science, McGill University, Chemistry (2005)
The macrolide antibiotic erythromycin A and its semisynthetic analogues have been among the most useful antibacterial agents for the treatment of infectious diseases. Using a recently developed chemical genetic strategy for precursor-directed biosynthesis and colony bioassay of 6-deoxyerythromycin D analogues, we identified a new class of alkynyl- and alkenyl-substituted macrolides with activities comparable to that of the natural product. Further analysis revealed a marked and unexpected dependence of antibiotic activity on the size and degree of unsaturation of the precursor. Based on these leads, we also report the precursor-directed biosynthesis of 15-propargyl erythromycin A, a novel antibiotic that not only is as potent as erythromycin A with respect to its ability to inhibit bacterial growth and cell-free ribosomal protein biosynthesis but also harbors an orthogonal functional group that is capable of facile chemical modification.
View details for DOI 10.1021/ja304682q
View details for Web of Science ID 000306724500075
View details for PubMedID 22741553
Macrolide antibacterial agents inhibit parasite proliferation by targeting the apicoplast ribosome. Motivated by the long-term goal of identifying antiparasitic macrolides that lack antibacterial activity, we have systematically analyzed the structure-activity relationships among erythromycin analogues and have also investigated the mechanism of action of selected compounds. Two lead compounds, N-benzylazithromycin (11) and N-phenylpropylazithromycin (30), were identified with significantly higher antiparasitic activity and lower antibacterial activity than erythromycin or azithromycin. Molecular modeling based on the cocrystal structure of azithromycin bound to the bacterial ribosome suggested that a substituent at the N-9 position of desmethylazithromycin could improve selectivity because of species-specific interactions with the ribosomal L22 protein. Like other macrolides, these lead compounds display a strong "delayed death phenotype"; however, their early effects on T. gondii replication are more pronounced.
View details for DOI 10.1021/jm101593u
View details for Web of Science ID 000289697800018
View details for PubMedID 21428405
Erythromycin and related macrolide antibiotics are widely used polyketide natural products. We have evolved an engineered biosynthetic pathway in Escherichia coli that yields erythromycin analogs from simple synthetic precursors. Multiple rounds of mutagenesis and screening led to the identification of new mutant strains with improved efficiency for precursor-directed biosynthesis. Genetic and biochemical analysis suggested that the phenotypically relevant alterations in these mutant strains were localized exclusively to the host-vector system, and not to the polyketide synthase. We also demonstrate the utility of this improved system through engineered biosynthesis of a novel alkynyl erythromycin derivative with comparable antibacterial activity to its natural counterpart. In addition to reinforcing the power of directed evolution for engineering macrolide biosynthesis, our studies have identified a new lead substance for investigating structure-function relationships in the bacterial ribosome.
View details for DOI 10.1038/ja.2010.129
View details for Web of Science ID 000287072300009
View details for PubMedID 21081955
A unit world model that has the potential to be used for the hazard assessment of both metal ions and organic chemicals is described and discussed, with an emphasis on the problems that arise when treating metal ions. It is based on the steady-state equilibrium criterion model that is designed to simulate the fate of organic chemicals in a 100,000-km(2) region and comprises four well-mixed compartments: Air, water, soil, and sediment. To be applicable to metal ions, modifications are required. The single soil and sediment layers should be replaced by two layers to accommodate aerobic and anaerobic conditions. The more complex and variable partitioning of metals resulting from dependence on pH, redox conditions, ionic oxidation state, and presence of sulfide also must be addressed, but preferably in a separate geochemical model, because these factors can result in nonlinearity. For metals, a dynamic as well as a steady-state model is desirable. It is shown that the resulting model can be applied to both organics and metals. Rather than seeking to apply the hazard criterion of persistence to metal ions, the model can be used to deduce a critical loading that results in a defined toxic end point, thus integrating the hazard criteria of persistence, toxicity, and possibly, bioaccumulation. This approach is applied illustratively to naphthalene as a typical organic substance and to four environmentally relevant metal ions. Results are discussed and recommendations made for further development. Specifically, the absence of metal degradation can result in large, steady-state quantities in soils and sediments corresponding to residence times of many centuries. Consequently, the dynamic calculations are more relevant for fate assessments of metals over a period of years, and more focus on the aquatic environment is justified.
View details for Web of Science ID 000249528000014
View details for PubMedID 17867881
The prevailing view is that long-range transport of semivolatile contaminants is primarily conducted by the physical system (e.g., winds, currents), and biological transport is typically ignored. Although this view may be correct in terms of bulk budgets and fluxes, it neglects the potential of animals to focus contaminants into foodwebs due to their behaviors and lifecycles. In particular, gregarious animals that biomagnify and bioaccumulate certain contaminants and then migrate and congregate can become the predominant pathway for contaminants in many circumstances. Fish and birds provide prominent examples for such behavior. This review examines the potential for biovector transport to expose populations to contaminants. In addition, we apply a modeling approach to compare the potential of biovector transport to other physical transport pathways for a hypothetical lake receiving large numbers of fish. We conclude that biovector transport should not be neglected when considering environmental risks of biomagnifying contaminants.
View details for DOI 10.1021/es061314a
View details for Web of Science ID 000244161600008
View details for PubMedID 17593703