caa a22 4500 445878851 CHVBK 20180317145536.0 cr unu---uuuuu 170323e20111101xx s 000 0 eng 10.1007/s11030-011-9333-2 doi (NATIONALLICENCE)springer-10.1007/s11030-011-9333-2 Potent antimicrobial small molecules screened as inhibitors of tyrosine recombinases and Holliday junction-resolving enzymes [Elektronische Daten] [Marc Rideout, Jeffrey Boldt, Gabriel Vahi-Ferguson, Peter Salamon, Adel Nefzi, John Ostresh, Marc Giulianotti, Clemencia Pinilla, Anca Segall] 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. Springer Science+Business Media B.V., 2011 Site-specific recombination nationallicence λ -Integrase nationallicence Holliday junction nationallicence Combinatorial libraries nationallicence DNA repair nationallicence Rideout Marc Department of Biology and Center for Microbial Sciences, San Diego State University, 92182, San Diego, CA, USA aut Boldt Jeffrey Department of Biology and Center for Microbial Sciences, San Diego State University, 92182, San Diego, CA, USA aut Vahi-Ferguson Gabriel Department of Biology and Center for Microbial Sciences, San Diego State University, 92182, San Diego, CA, USA aut Salamon Peter Department of Mathematics and Statistics, San Diego State University, 92182, San Diego, CA, USA aut Nefzi Adel Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, 34987-2352, Port St. Lucie, FL, USA aut Ostresh John Torrey Pines Institute for Molecular Studies, 3550 General Atomics Court, 2-129, 92121-1120, San Diego, CA, USA aut Giulianotti Marc Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, 34987-2352, Port St. Lucie, FL, USA aut Pinilla Clemencia Torrey Pines Institute for Molecular Studies, 3550 General Atomics Court, 2-129, 92121-1120, San Diego, CA, USA aut Segall Anca Department of Biology and Center for Microbial Sciences, San Diego State University, 92182, San Diego, CA, USA aut Molecular Diversity Springer Netherlands 15/4(2011-11-01), 989-1005 1381-1991 15:4<989 2011 15 11030 https://doi.org/10.1007/s11030-011-9333-2 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s11030-011-9333-2 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Rideout Marc Department of Biology and Center for Microbial Sciences, San Diego State University, 92182, San Diego, CA, USA aut NATIONALLICENCE 700 1- Boldt Jeffrey Department of Biology and Center for Microbial Sciences, San Diego State University, 92182, San Diego, CA, USA aut NATIONALLICENCE 700 1- Vahi-Ferguson Gabriel Department of Biology and Center for Microbial Sciences, San Diego State University, 92182, San Diego, CA, USA aut NATIONALLICENCE 700 1- Salamon Peter Department of Mathematics and Statistics, San Diego State University, 92182, San Diego, CA, USA aut NATIONALLICENCE 700 1- Nefzi Adel Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, 34987-2352, Port St. Lucie, FL, USA aut NATIONALLICENCE 700 1- Ostresh John Torrey Pines Institute for Molecular Studies, 3550 General Atomics Court, 2-129, 92121-1120, San Diego, CA, USA aut NATIONALLICENCE 700 1- Giulianotti Marc Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, 34987-2352, Port St. Lucie, FL, USA aut NATIONALLICENCE 700 1- Pinilla Clemencia Torrey Pines Institute for Molecular Studies, 3550 General Atomics Court, 2-129, 92121-1120, San Diego, CA, USA aut NATIONALLICENCE 700 1- Segall Anca Department of Biology and Center for Microbial Sciences, San Diego State University, 92182, San Diego, CA, USA aut NATIONALLICENCE 773 0- Molecular Diversity Springer Netherlands 15/4(2011-11-01), 989-1005 1381-1991 15:4<989 2011 15 11030 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer