Professional Education
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Doctor of Philosophy, University of Wisconsin Madison (2022)
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Bachelor of Arts, Macalester College, Applied Mathematics, Chemistry (2017)
All Publications
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Biguanide-Vancomycin Conjugates are Effective Broad-Spectrum Antibiotics against Actively Growing and Biofilm-Associated Gram-Positive and Gram-Negative ESKAPE Pathogens and Mycobacteria.
Journal of the American Chemical Society
2024
Abstract
Strategies to increase the efficacy and/or expand the spectrum of activity of existing antibiotics provide a potentially fast path to clinically address the growing crisis of antibiotic-resistant infections. Here, we report the synthesis, antibacterial efficacy, and mechanistic activity of an unprecedented class of biguanide-antibiotic conjugates. Our lead biguanide-vancomycin conjugate, V-C6-Bg-PhCl (5e), induces highly effective cell killing with up to a 2 orders-of-magnitude improvement over its parent compound, vancomycin (V), against vancomycin-resistant enterococcus. V-C6-Bg-PhCl (5e) also exhibits improved activity against mycobacteria and each of the ESKAPE pathogens, including the Gram-negative organisms. Furthermore, we uncover broad-spectrum killing activity against biofilm-associated Gram-positive and Gram-negative bacteria as well as mycobacteria not observed for clinically used antibiotics such as oritavancin. Mode-of-action studies reveal that vancomycin-like cell wall synthesis inhibition with improved efficacy attributed to enhanced engagement at vancomycin binding sites through biguanide association with relevant cell-surface anions for Gram-positive and Gram-negative bacteria. Due to its potency, remarkably broad activity, and lack of acute mammalian cell toxicity, V-C6-Bg-PhCl (5e) is a promising candidate for treating antibiotic-resistant infections and notoriously difficult-to-treat slowly growing and antibiotic-tolerant bacteria associated with chronic and often incurable infections. More generally, this study offers a new strategy (biguanidinylation) to enhance antibiotic activity and facilitate clinical entry.
View details for DOI 10.1021/jacs.4c06520
View details for PubMedID 39088791
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Vancomycin-Polyguanidino Dendrimer Conjugates Inhibit Growth of Antibiotic-Resistant Gram-Positive and Gram-Negative Bacteria and Eradicate Biofilm-AssociatedS.aureus.
ACS infectious diseases
2024
Abstract
The global challenge of antibiotic resistance necessitates the introduction of more effective antibiotics. Here we report a potentially general design strategy, exemplified with vancomycin, that improves and expands antibiotic performance. Vancomycin is one of the most important antibiotics in use today for the treatment of Gram-positive infections. However, it fails to eradicate difficult-to-treat biofilm populations. Vancomycin is also ineffective in killing Gram-negative bacteria due to its inability to breach the outer membrane. Inspired by our seminal studies on cell penetrating guanidinium-rich transporters (e.g., octaarginine), we recently introduced vancomycin conjugates that effectively eradicate Gram-positive biofilm bacteria, persister cells and vancomycin-resistant enterococci (with V-r8, vancomycin-octaarginine), and Gram-negative pathogens (with V-R, vancomycin-arginine). Having shown previously that the spatial array (linear versus dendrimeric) of multiple guanidinium groups affects cell permeation, we report here for the first time vancomycin conjugates with dendrimerically displayed guanidinium groups that exhibit superior efficacy and breadth, presenting the best activity of V-r8 and V-R in single broad-spectrum compounds active against ESKAPE pathogens. Mode-of-action studies reveal cell-surface activity and enhanced vancomycin-like killing. The vancomycin-polyguanidino dendrimer conjugates exhibit no acute mammalian cell toxicity or hemolytic activity. Our study introduces a new class of broad-spectrum vancomycin derivatives and a general strategy to improve or expand antibiotic performance through combined mode-of-action and function-oriented design studies.
View details for DOI 10.1021/acsinfecdis.3c00168
View details for PubMedID 38252999
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CPMAS NMR platform for direct compositional analysis of mycobacterial cell-wall complexes and whole cells.
Journal of magnetic resonance open
2023; 16-17
Abstract
Tuberculosis and non-tuberculosis mycobacterial infections are rising each year and often result in chronic incurable disease. Important antibiotics target cell-wall biosynthesis, yet some mycobacteria are alarmingly resistant or tolerant to currently available antibiotics. This resistance is often attributed to assumed differences in composition of the complex cell wall of different mycobacterial strains and species. However, due to the highly crosslinked and insoluble nature of mycobacterial cell walls, direct comparative determinations of cell-wall composition pose a challenge to analysis through conventional biochemical analyses. We introduce an approach to directly observe the chemical composition of mycobacterial cell walls using solid-state NMR spectroscopy. 13C CPMAS spectra are provided of individual components (peptidoglycan, arabinogalactan, and mycolic acids) and of in situ cell-wall complexes. We assigned the spectroscopic contributions of each component in the cell-wall spectrum. We uncovered a higher arabinogalactan-to-peptidoglycan ratio in the cell wall of M. abscessus, an organism noted for its antibiotic resistance, relative to M. smegmatis. Furthermore, differentiating influences of different types of cell-wall targeting antibiotics were observed in spectra of antibiotic-treated whole cells. This platform will be of value in evaluating cell-wall composition and antibiotic activity among different mycobacteria and in considering the most effective combination treatment regimens.
View details for DOI 10.1016/j.jmro.2023.100127
View details for PubMedID 38125335
View details for PubMedCentralID PMC10732466
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Tailoring Reaction Selectivity by Modulating a Catalytic Diad on a Foldamer Scaffold (vol 144, pg 2225, 2022)
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
2022; 144 (34): 15908
View details for DOI 10.1021/jacs.2c08194
View details for Web of Science ID 000841617400001
View details for PubMedID 35973103
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Structural and functional diversity among agonist-bound states of the GLP-1 receptor
NATURE CHEMICAL BIOLOGY
2022; 18 (3): 256-+
Abstract
Recent advances in G-protein-coupled receptor (GPCR) structural elucidation have strengthened previous hypotheses that multidimensional signal propagation mediated by these receptors depends, in part, on their conformational mobility; however, the relationship between receptor function and static structures is inherently uncertain. Here, we examine the contribution of peptide agonist conformational plasticity to activation of the glucagon-like peptide 1 receptor (GLP-1R), an important clinical target. We use variants of the peptides GLP-1 and exendin-4 (Ex4) to explore the interplay between helical propensity near the agonist N terminus and the ability to bind to and activate the receptor. Cryo-EM analysis of a complex involving an Ex4 analog, the GLP-1R and Gs heterotrimer revealed two receptor conformers with distinct modes of peptide-receptor engagement. Our functional and structural data, along with molecular dynamics (MD) simulations, suggest that receptor conformational dynamics associated with flexibility of the peptide N-terminal activation domain may be a key determinant of agonist efficacy.
View details for DOI 10.1038/s41589-021-00945-w
View details for Web of Science ID 000733335800005
View details for PubMedID 34937906
View details for PubMedCentralID PMC8950777
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Comparisons of beta-Hairpin Propensity Among Peptides with Homochiral or Heterochiral Strands
CHEMBIOCHEM
2021; 22 (18): 2772-2776
Abstract
Assemblies of racemic β-sheet-forming peptides have attracted attention for biomedical applications because racemic forms of peptides can self-associate more avidly than do single enantiomers. In 1953, Pauling and Corey proposed "rippled β-sheet" modes of H-bond-mediated interstrand assembly for alternating L- and D-peptide strands; this structural hypothesis was complementary to their proposal of "pleated β-sheet" assembly for L-peptides. Although no high-resolution structure has been reported for a rippled β-sheet, there is strong evidence for the occurrence of rippled β-sheets in some racemic peptide assemblies. Here we compare propensities of peptide diastereomers in aqueous solution to form a minimum increment of β-sheet in which two antiparallel strands associate. β-Hairpin folding is observed for homochiral peptides with aligned nonpolar side chains, but no β-hairpin population can be detected for diastereomers in which one strand contains L residues and the other contains D residues. These observations suggest that rippled β-sheet assemblies are stabilized by interactions between β-sheet layers rather than interactions within these layers.
View details for DOI 10.1002/cbic.202100324
View details for Web of Science ID 000679561600001
View details for PubMedID 34288305
View details for PubMedCentralID PMC8486351
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The role of beta-hairpin conformation in ester hydrolysis peptide catalysts based on a TrpZip scaffold
RSC ADVANCES
2021; 11 (38): 23714-23718
Abstract
To explore the role of peptide conformation on catalytic activity in the context of ester hydrolysis catalysts, pairs of sequences were designed that contained or lacked β-hairpin character. For the hydrolysis of para-nitrophenylacetate in aqueous media, we found small but consistent trends wherein His-containing sequences based on a TrpZip scaffold showed higher catalytic activity without β-hairpin character.
View details for DOI 10.1039/d1ra04288b
View details for Web of Science ID 000671447100056
View details for PubMedID 34354822
View details for PubMedCentralID PMC8285361
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Catalytic Intramolecular Conjugate Additions of Aldehyde-Derived Enamines to alpha,beta-Unsaturated Esters
ORGANIC LETTERS
2020; 22 (11): 4568-4573
Abstract
We report a pairing of known catalysts that enables intramolecular conjugate additions of aldehyde-derived enamines to α,β-unsaturated esters. Despite extensive prior exploration of conjugate additions of aldehyde-derived enamines, catalytic conjugate additions to unactivated enoate esters are unprecedented. Achieving enantioselective and diastereoselective six-membered ring formation requires the coordinated action of a chiral pyrrolidine, for nucleophilic activation of the aldehyde via enamine formation, and a hydrogen bond donor, for electrophilic activation of the enoate ester. Proper selection of the hydrogen bond donor is essential for chemoselectivity, which requires minimizing competition from homoaldol reaction. Utility is demonstrated in a six-step synthesis of (-)-yohimbane from cycloheptene.
View details for DOI 10.1021/acs.orglett.0c01666
View details for Web of Science ID 000538848600099
View details for PubMedID 32460501
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Foldamer-templated catalysis of macrocycle formation
SCIENCE
2019; 366 (6472): 1528-+
Abstract
Macrocycles, compounds containing a ring of 12 or more atoms, find use in human medicine, fragrances, and biological ion sensing. The efficient preparation of macrocycles is a fundamental challenge in synthetic organic chemistry because the high entropic cost of large-ring closure allows undesired intermolecular reactions to compete. Here, we present a bioinspired strategy for macrocycle formation through carbon-carbon bond formation. The process relies on a catalytic oligomer containing α- and β-amino acid residues to template the ring-closing process. The α/β-peptide foldamer adopts a helical conformation that displays a catalytic primary amine-secondary amine diad in a specific three-dimensional arrangement. This catalyst promotes aldol reactions that form rings containing 14 to 22 atoms. Utility is demonstrated in the synthesis of the natural product robustol.
View details for DOI 10.1126/science.aax7344
View details for Web of Science ID 000503861000058
View details for PubMedID 31857487
View details for PubMedCentralID PMC7956107
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A colorimetric competitive displacement assay for the evaluation of catalytic peptides
ORGANIC & BIOMOLECULAR CHEMISTRY
2017; 15 (48): 10160-10163
Abstract
An indicator displacement assay has been adapted to detect the diol products of the aldol reaction between 4-nitrobenzaldehyde and hydroxyacetone in crude reaction mixtures. This provides a rapid colorimetric method of detecting product formation and thus evaluating potential catalysts, which is demonstrated using multiple catalytic peptides.
View details for DOI 10.1039/c7ob02032e
View details for Web of Science ID 000418070800005
View details for PubMedID 29182189
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Pre-monomer peptidomimetic synthesis using thiol-ene click chemistry
AMER CHEMICAL SOC. 2017
View details for Web of Science ID 000430568505280