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Potent antimicrobial small molecules screened as inhibitors of tyrosine recombinases and Holliday junction-resolving enzymes

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Abstract

Holliday junctions (HJs) are critical intermediates in many recombination-dependent DNA repair pathways. Our lab has previously identified several hexameric peptides that target HJ intermediates formed in DNA recombination reactions. One of the most potent peptides, WRWYCR, is active as a homodimer and has shown bactericidal activity partly because of its ability to interfere with DNA repair proteins that act upon HJs. To increase the possibility of developing a therapeutic targeting DNA repair, we searched for small molecule inhibitors that were functional surrogates of the peptides. Initial screens of heterocyclic small molecule libraries resulted in the identification of several N-methyl aminocyclic thiourea inhibitors. Like the peptides, these inhibitors trapped HJs formed during recombination reactions in vitro, but were less potent than the peptides in biochemical assays and had little antibacterial activity. In this study, we describe the screening of a second set of libraries containing somewhat larger and more symmetrical scaffolds in an effort to mimic the symmetry of a WRWYCR homodimer and its target. From this screen, we identified several pyrrolidine bis-cyclic guanidine inhibitors that also interfere with processing of HJs in vitro and are potent inhibitors of Gram-negative and especially Gram-positive bacterial growth. These molecules are proof-of-principle of a class of compounds with novel activities, which may in the future be developed into a new class of antibiotics that will expand the available choices for therapy against drug-resistant bacteria.

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Author notes

  1. Jeffrey L. Boldt

    Present address: Genomatica, Inc., 10520 Wateridge Circle, San Diego, CA, 92121, USA

Authors and Affiliations

  1. Department of Biology and Center for Microbial Sciences, San Diego State University, San Diego, CA, 92182, USA

    Marc C. Rideout, Jeffrey L. Boldt, Gabriel Vahi-Ferguson & Anca M. Segall

  2. Department of Mathematics and Statistics, San Diego State University, San Diego, CA, 92182, USA

    Gabriel Vahi-Ferguson & Peter Salamon

  3. Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL, 34987-2352, USA

    Adel Nefzi & Marc Giulianotti

  4. Torrey Pines Institute for Molecular Studies, 3550 General Atomics Court, 2-129, San Diego, CA, 92121-1120, USA

    John M. Ostresh & Clemencia Pinilla

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  1. Marc C. Rideout
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Corresponding author

Correspondence to Anca M. Segall.

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The first two authors should be considered co-first authors.

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Rideout, M.C., Boldt, J.L., Vahi-Ferguson, G. et al. Potent antimicrobial small molecules screened as inhibitors of tyrosine recombinases and Holliday junction-resolving enzymes. Mol Divers 15, 989–1005 (2011). https://doi.org/10.1007/s11030-011-9333-2

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