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Meyer, Elisabeth

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Meyer

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Elisabeth

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Meyer, Elisabeth

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2013 - 20192

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    Euler buckling and nonlinear kinking of double-stranded DNA
    (Oxford University Press, 2013) Fields, Alexander P.; Meyer, Elisabeth; Cohen, Adam
    The bending stiffness of double-stranded DNA (dsDNA) at high curvatures is fundamental to its biological activity, yet this regime has been difficult to probe experimentally, and literature results have not been consistent. We created a ‘molecular vise’ in which base-pairing interactions generated a compressive force on sub-persistence length segments of dsDNA. Short dsDNA strands (<41 base pairs) resisted this force and remained straight; longer strands became bent, a phenomenon called ‘Euler buckling’. We monitored the buckling transition via Förster Resonance Energy Transfer (FRET) between appended fluorophores. For low-to-moderate concentrations of monovalent salt (up to ∼150 mM), our results are in quantitative agreement with the worm-like chain (WLC) model of DNA elasticity, without the need to invoke any ‘kinked’ states. Greater concentrations of monovalent salts or 1 mM Mg2+ induced an apparent softening of the dsDNA, which was best accounted for by a kink in the region of highest curvature. We tested the effects of all single-nucleotide mismatches on the DNA bending. Remarkably, the propensity to kink correlated with the thermodynamic destabilization of the mismatched DNA relative the perfectly complementary strand, suggesting that the kinked state is locally melted. The molecular vise is exquisitely sensitive to the sequence-dependent linear and nonlinear elastic properties of dsDNA.
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    Large-Scale Chemical–genetics Yields New M. Tuberculosis Inhibitor Classes
    (Springer Science and Business Media LLC, 2019-06-19) LaVerriere, Emily; Meyer, Elisabeth; Kawate, Tomohiko; Gomez, James; Gardner, Michelle; Cigarroa Kennedy, Sofia; Wakabayashi, Shoko; Watson, Christopher; Fitzgerald, Michael; Johnson, Eachan; Office, Emma; Stanley, Mary; Audette, Rebecca; Bandyopadhyay, Nirmalya; Betancourt, Natalia; Delano, Kayla; Da Silva, Israel; Davis, Joshua; Gallo, Christina; Golas, Aaron; Guinn, Kristine; Korn, Rebecca; McConnell, Jennifer; Moss, Caitlin; Murphy, Kenan; Nietupski, Raymond; Papavinasasundaram, Kadamba; Pinkham, Jessica; Pino, Paula; Proulx, Megan; Ruecker, Nadine; Song, Naomi; Thompson, Matthew; Trujillo, Carolina; Metcalf-Wallach, Joshua; Ioerger, Thomas; Lander, Eric; Hubbard, Brian; Serrano-Wu, Michael; Ehrt, Sabine; Rubin, Eric; Sassetti, Christopher; Schnappinger, Dirk; Hung, Deborah
    New antibiotics are needed to combat rising resistance, with new Mycobacterium tuberculosis (Mtb) drugs of highest priority. Conventional whole-cell and biochemical antibiotic screens have failed. We developed a novel strategy termed PROSPECT (PRimary screening Of Strains to Prioritize Expanded Chemistry and Targets) in which we screen compounds against pools of strains depleted for essential bacterial targets. We engineered strains targeting 474 Mtb essential genes and screened pools of 100-150 strains against activity-enriched and unbiased compounds libraries, probing >8.5-million chemical-genetic interactions. Primary screens identified >10-fold more hits than screening wild-type Mtb alone, with chemical-genetic interactions providing immediate, direct target insight. We identified >40 novel compounds targeting DNA gyrase, cell wall, tryptophan, folate biosynthesis, and RNA polymerase, as well as inhibitors of a novel target EfpA. Chemical optimization yielded EfpA inhibitors with potent wild-type activity, thus demonstrating PROSPECT’s ability to yield inhibitors against novel targets which would have eluded conventional drug discovery.