{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T09:07:22Z","timestamp":1788858442394,"version":"build-2803163510"},"reference-count":29,"publisher":"American Chemical Society (ACS)","issue":"13","license":[{"start":{"date-parts":[[2015,5,14]],"date-time":"2015-05-14T00:00:00Z","timestamp":1431561600000},"content-version":"vor","delay-in-days":365,"URL":"https:\/\/pubs.acs.org\/page\/policy\/authorchoice_termsofuse.html"}],"funder":[{"DOI":"10.13039\/501100001677","name":"National institute of Health and Medical Research","doi-asserted-by":"publisher","award":["GM065307, CA158191, GM08326, GM31749 and HD071600"],"award-info":[{"award-number":["GM065307, CA158191, GM08326, GM31749 and HD071600"]}],"id":[{"id":"10.13039\/501100001677","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["MCB-1020765"],"award-info":[{"award-number":["MCB-1020765"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,7,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>There is a significant need for new antibiotics due to the rise in drug resistance. Drugs such as methicillin and vancomycin target bacterial cell wall biosynthesis, but methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE) have now arisen and are of major concern. Inhibitors acting on new targets in cell wall biosynthesis are thus of particular interest since they might also restore sensitivity to existing drugs, and the cis-prenyl transferase undecaprenyl diphosphate synthase (UPPS), essential for lipid I, lipid II, and thus, peptidoglycan biosynthesis, is one such target. We used 12 UPPS crystal structures to validate virtual screening models and then assayed 100 virtual hits (from 450,000 compounds) against UPPS from S. aureus and Escherichia coli. The most promising inhibitors (IC50 \u223c2 \u03bcM, Ki \u223c300 nM) had activity against MRSA, Listeria monocytogenes, Bacillus anthracis, and a vancomycin-resistant Enterococcus sp. with MIC or IC50 values in the 0.25\u20134 \u03bcg\/mL range. Moreover, one compound (1), a rhodanine with close structural similarity to the commercial diabetes drug epalrestat, exhibited good activity as well as a fractional inhibitory concentration index (FICI) of 0.1 with methicillin against the community-acquired MRSA USA300 strain, indicating strong synergism.<\/jats:p>","DOI":"10.1021\/jm5004649","type":"journal-article","created":{"date-parts":[[2014,5,14]],"date-time":"2014-05-14T13:51:06Z","timestamp":1400075466000},"page":"5693-5701","source":"Crossref","is-referenced-by-count":44,"title":["Undecaprenyl Diphosphate Synthase Inhibitors: Antibacterial\nDrug Leads"],"prefix":"10.1021","volume":"57","author":[{"given":"William","family":"Sinko","sequence":"first","affiliation":[{"name":"University of California San Diego , , , ,","place":["La Jolla, California, United States, 92093-0365"]},{"name":"University of California San Diego , , , ,","place":["La Jolla, California, United States, 92093-0365"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Wang","sequence":"additional","affiliation":[{"name":"University of Illinois , , ,","place":["Urbana, Illinois, United States, 61801"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zhu","sequence":"additional","affiliation":[{"name":"University of Illinois , , ,","place":["Urbana, Illinois, United States, 61801"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yonghui","family":"Zhang","sequence":"additional","affiliation":[{"name":"University of Illinois , , ,","place":["Urbana, Illinois, United States, 61801"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ferran","family":"Feixas","sequence":"additional","affiliation":[{"name":"University of California San Diego , , , ,","place":["La Jolla, California, United States, 92093-0365"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Courtney L.","family":"Cox","sequence":"additional","affiliation":[{"name":"University of Illinois , , , ,","place":["Urbana, Illinois, United States, 61801"]},{"name":"University of Illinois , , , ,","place":["Urbana, Illinois, United States, 61801"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas A.","family":"Mitchell","sequence":"additional","affiliation":[{"name":"University of Illinois , , ,","place":["Urbana, Illinois, United States, 61801"]},{"name":"University of Illinois , , , ,","place":["Urbana, Illinois, United States, 61801"]},{"name":"University of Illinois , , , ,","place":["Urbana, Illinois, United States, 61801"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Oldfield","sequence":"additional","affiliation":[{"name":"University of Illinois , , ,","place":["Urbana, Illinois, United States, 61801"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Andrew","family":"McCammon","sequence":"additional","affiliation":[{"name":"University of California San Diego , , , ,","place":["La Jolla, California, United States, 92093-0365"]},{"name":"University of California San Diego , , , ,","place":["La Jolla, California, United States, 92093-0365"]},{"name":"University of California San Diego , , , ,","place":["La Jolla, California, United States, 92093-0365"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2014,5,14]]},"reference":[{"key":"2026090313582753500_cit1","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1126\/science.1176667","article-title":"Antibiotics for\nemerging pathogens","volume":"325","author":"Fischbach","year":"2009","journal-title":"Science"},{"key":"2026090313582753500_cit2","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1038\/ja.2011.44","article-title":"Antibiotics in the clinical pipeline\nin 2011","volume":"64","author":"Butler","year":"2011","journal-title":"J. Antibiot."},{"key":"2026090313582753500_cit3","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1128\/MMBR.00016-07","article-title":"Lipid intermediates in the biosynthesis of bacterial\npeptidoglycan","volume":"71","author":"van Heijenoort","year":"2007","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"2026090313582753500_cit4","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1128\/JB.181.2.483-492.1999","article-title":"Use of genomics\nto identify bacterial undecaprenyl pyrophosphate synthetase: cloning,\nexpression, and characterization of the essential uppS gene","volume":"181","author":"Apfel","year":"1999","journal-title":"J. Bacteriol."},{"key":"2026090313582753500_cit5","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1038\/nrd2201","article-title":"Drugs for\nbad bugs: confronting the challenges of antibacterial discovery","volume":"6","author":"Payne","year":"2007","journal-title":"Nat. Rev. Drug Discovery"},{"key":"2026090313582753500_cit6","doi-asserted-by":"crossref","first-page":"1840","DOI":"10.1016\/j.bmcl.2008.02.009","article-title":"Design and structure-activity relationships of potent\nand selective inhibitors of undecaprenyl pyrophosphate synthase (UPPS):\ntetramic, tetronic acids and dihydropyridin-2-ones","volume":"18","author":"Peukert","year":"2008","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"2026090313582753500_cit7","doi-asserted-by":"crossref","first-page":"5366","DOI":"10.1021\/bi100523c","article-title":"Biophysical investigation\nof the mode of inhibition of tetramic acids, the allosteric inhibitors\nof undecaprenyl pyrophosphate synthase","volume":"49","author":"Lee","year":"2010","journal-title":"Biochemistry"},{"key":"2026090313582753500_cit8","doi-asserted-by":"crossref","first-page":"10022","DOI":"10.1073\/pnas.0702254104","article-title":"Bisphosphonates\ntarget multiple sites in both cis- and trans-prenyltransferases","volume":"104","author":"Guo","year":"2007","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2026090313582753500_cit9","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1111\/j.1747-0285.2011.01164.x","article-title":"Non-bisphosphonate inhibitors of\nisoprenoid biosynthesis identified via computer-aided drug design","volume":"78","author":"Durrant","year":"2011","journal-title":"Chem. Biol. Drug Des."},{"key":"2026090313582753500_cit10","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1021\/ml300038t","article-title":"HIV-1 integrase inhibitor-inspired\nantibacterials targeting isoprenoid biosynthesis","volume":"3","author":"Zhang","year":"2012","journal-title":"ACS Med. Chem. Lett."},{"key":"2026090313582753500_cit11","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1111\/cbdd.12121","article-title":"Farnesyl\ndiphosphate synthase inhibitors from in silico screening","volume":"81","author":"Lindert","year":"2013","journal-title":"Chem. Biol. Drug Des."},{"key":"2026090313582753500_cit12","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1073\/pnas.1219899110","article-title":"Antibacterial drug leads targeting isoprenoid biosynthesis","volume":"110","author":"Zhu","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2026090313582753500_cit13","doi-asserted-by":"crossref","first-page":"1750","DOI":"10.1021\/jm030644s","article-title":"Glide: A new approach for rapid,\naccurate docking and scoring. 2. Enrichment factors in database screening","volume":"47","author":"Halgren","year":"2004","journal-title":"J. Med. Chem."},{"key":"2026090313582753500_cit14","doi-asserted-by":"crossref","first-page":"6177","DOI":"10.1021\/jm051256o","article-title":"Extra precision\nglide: docking and scoring incorporating a model of hydrophobic enclosure\nfor protein-ligand complexes","volume":"49","author":"Friesner","year":"2006","journal-title":"J. Med. Chem."},{"key":"2026090313582753500_cit15","volume-title":"Suite\n2011: Glide, version 5.7","author":"Schro\u0308dinger","year":"2011"},{"key":"2026090313582753500_cit16","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1007\/s10822-013-9644-8","article-title":"Protein and ligand preparation: parameters,\nprotocols,\nand influence on virtual screening enrichments","volume":"27","author":"Sastry","year":"2013","journal-title":"J. Comput.-Aided Mol. Des."},{"key":"2026090313582753500_cit17","volume-title":"Suite 2012: Canvas\nversion 1.5","year":"2012"},{"key":"2026090313582753500_cit18","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.jmgm.2010.05.008","article-title":"Analysis and comparison\nof 2D fingerprints: insights into database screening performance using\neight fingerprint methods","volume":"29","author":"Duan","year":"2010","journal-title":"J. Mol. Graphics\nModell."},{"key":"2026090313582753500_cit19","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1021\/ci100062n","article-title":"Large-scale systematic\nanalysis of 2D fingerprint methods and parameters to improve virtual\nscreening enrichments","volume":"50","author":"Sastry","year":"2010","journal-title":"J. Chem. Inf. Model."},{"key":"2026090313582753500_cit20","doi-asserted-by":"crossref","first-page":"4884","DOI":"10.1073\/pnas.89.11.4884","article-title":"A continuous\nspectrophotometric assay for inorganic phosphate and for measuring\nphosphate release kinetics in biological systems","volume":"89","author":"Webb","year":"1992","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2026090313582753500_cit21","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1177\/1087057103258185","article-title":"The effect\nof triton concentration on the activity\nof undecaprenyl pyrophosphate synthase inhibitors","volume":"8","author":"Li","year":"2003","journal-title":"J. Biomol. Screening"},{"key":"2026090313582753500_cit22","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1021\/cb200339d","article-title":"Structure determination\nand interception of biosynthetic intermediates for the plantazolicin\nclass of highly discriminating antibiotics","volume":"6","author":"Molohon","year":"2011","journal-title":"ACS Chem. Biol."},{"key":"2026090313582753500_cit23","doi-asserted-by":"crossref","first-page":"7331","DOI":"10.1021\/jm060492b","article-title":"Isoprenoid\nbiosynthesis as a drug target: bisphosphonate inhibition of Escherichia\ncoli K12 growth and synergistic effects of fosmidomycin","volume":"49","author":"Leon","year":"2006","journal-title":"J. Med. Chem."},{"key":"2026090313582753500_cit24","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1111\/j.1747-0285.2011.01101.x","article-title":"Applying molecular\ndynamics simulations to identify rarely sampled ligand bound conformational\nstates of undecaprenyl pyrophosphate synthase, an antibacterial target","volume":"77","author":"Sinko","year":"2011","journal-title":"Chem. Biol. Drug Des."},{"key":"2026090313582753500_cit25","doi-asserted-by":"crossref","first-page":"2534","DOI":"10.1021\/jm049092j","article-title":"Virtual\nscreening workflow development guided by the \u201creceiver operating\ncharacteristic\u201d curve approach. Application to high-throughput\ndocking on metabotropic glutamate receptor subtype 4","volume":"48","author":"Triballeau","year":"2005","journal-title":"J. Med. Chem."},{"key":"2026090313582753500_cit26","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1007\/978-1-61779-465-0_13","article-title":"How to benchmark methods for structure-based virtual screening of\nlarge compound libraries","volume":"819","author":"Christofferson","year":"2012","journal-title":"Methods Mol. Biol."},{"key":"2026090313582753500_cit27","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1592\/phco.28.5.646","article-title":"Epalrestat: an aldose\nreductase inhibitor for the treatment\nof diabetic neuropathy","volume":"28","author":"Ramirez","year":"2008","journal-title":"Pharmacotherapy"},{"key":"2026090313582753500_cit28","doi-asserted-by":"crossref","first-page":"2719","DOI":"10.1021\/jm901137j","article-title":"New substructure\nfilters for removal of pan assay interference\ncompounds (PAINS) from screening libraries and for their exclusion\nin bioassays","volume":"53","author":"Baell","year":"2010","journal-title":"J. Med. Chem."},{"key":"2026090313582753500_cit29","doi-asserted-by":"crossref","first-page":"3126","DOI":"10.1021\/jm500131s","article-title":"Multi-target drug discovery\nfor tuberculosis and other\ninfectious diseases","volume":"57","author":"Li","year":"2014","journal-title":"J. Med. Chem."}],"container-title":["Journal of Medicinal Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/jm5004649","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jmcmar\/article-pdf\/57\/13\/5693\/12875777\/jm5004649.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jmcmar\/article-pdf\/57\/13\/5693\/12875777\/jm5004649.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T08:12:49Z","timestamp":1788855169000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jmcmar\/article\/57\/13\/5693\/1300486\/Undecaprenyl-Diphosphate-Synthase-Inhibitors"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,5,14]]},"references-count":29,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2014,5,14]]},"published-print":{"date-parts":[[2014,7,10]]}},"URL":"https:\/\/doi.org\/10.1021\/jm5004649","relation":{},"ISSN":["0022-2623","1520-4804"],"issn-type":[{"value":"0022-2623","type":"print"},{"value":"1520-4804","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,5,14]]}}}