{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,29]],"date-time":"2026-03-29T11:11:08Z","timestamp":1774782668343,"version":"3.50.1"},"reference-count":29,"publisher":"American Society for Microbiology","issue":"4","license":[{"start":{"date-parts":[[2015,4,1]],"date-time":"2015-04-01T00:00:00Z","timestamp":1427846400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2015,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            In a loss-of-viability screen using small molecules against methicillin-resistant\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Staphylococcus aureus<\/jats:named-content>\n            (MRSA) strain USA300 with a sub-MIC of a \u03b2-lactam, we found a small molecule, designated DNAC-1, which potentiated the effect of oxacillin (i.e., the MIC of oxacillin decreased from 64 to 0.25 \u03bcg\/ml). Fluorescence microscopy indicated a disruption in the membrane structures within 15 min of exposure to DNAC-1 at 2\u00d7 MIC. This permeabilization was accompanied by a rapid loss of membrane potential, as monitored by use of the DiOC\n            <jats:sub>2<\/jats:sub>\n            (3,3\u2032-diethyloxacarbocyanine iodide) dye. Macromolecular analysis showed the inhibition of staphylococcal cell wall synthesis by DNAC-1. Transmission electron microscopy of treated MRSA USA300 cells revealed a slightly thicker cell wall, together with mesosome-like projections into the cytosol. The exposure of USA300 cells to DNAC-1 was associated with the mislocalization of FtsZ accompanied by the localization of penicillin-binding protein 2 (PBP2) and PBP4 away from the septum, as well as mild activation of the\n            <jats:italic>vraRS<\/jats:italic>\n            -mediated cell wall stress response. However, DNAC-1 does not have any generalized toxicity toward mammalian host cells. DNAC-1 in combination with ceftriaxone is also effective against an assortment of Gram-negative pathogens. Using a murine subcutaneous coinjection model with 10\n            <jats:sup>8<\/jats:sup>\n            CFU of USA300 as a challenge inoculum, DNAC-1 alone or DNAC-1 with a sub-MIC of oxacillin resulted in a 6-log reduction in bacterial load and decreased abscess formation compared to the untreated control. We propose that DNAC-1, by exerting a bimodal effect on the cell membrane and cell wall, is a viable candidate in the development of combination therapy against many common bacterial pathogens.\n          <\/jats:p>","DOI":"10.1128\/aac.04164-14","type":"journal-article","created":{"date-parts":[[2015,3,11]],"date-time":"2015-03-11T16:36:49Z","timestamp":1426091809000},"page":"1876-1885","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":25,"title":["Characterization of a Novel Small Molecule That Potentiates \u03b2-Lactam Activity against Gram-Positive and Gram-Negative Pathogens"],"prefix":"10.1128","volume":"59","author":[{"given":"Dhanalakshmi R.","family":"Nair","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA"}]},{"given":"Jo\u00e3o M.","family":"Monteiro","sequence":"additional","affiliation":[{"name":"Bacterial Cell Biology Laboratory, Instituto de Technologia Qu\u00edmica e Biol\u00f3gica, Universidade Nova de Lisboa, Oeiras, Portugal"}]},{"given":"Guido","family":"Memmi","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA"}]},{"given":"Jane","family":"Thanassi","sequence":"additional","affiliation":[{"name":"Achillion Pharmaceuticals, New Haven, Connecticut, USA"}]},{"given":"Michael","family":"Pucci","sequence":"additional","affiliation":[{"name":"Achillion Pharmaceuticals, New Haven, Connecticut, USA"}]},{"given":"Joseph","family":"Schwartzman","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA"}]},{"given":"Mariana G.","family":"Pinho","sequence":"additional","affiliation":[{"name":"Bacterial Cell Biology Laboratory, Instituto de Technologia Qu\u00edmica e Biol\u00f3gica, Universidade Nova de Lisboa, Oeiras, Portugal"}]},{"given":"Ambrose L.","family":"Cheung","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(06)68853-3"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1086\/420937"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.13-237610"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1021\/cb300413m"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00049-08"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0002351"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2004.04420.x"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2014.07.029"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3003592"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.femsle.2004.09.038"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/jb.174.15.4952-4959.1992"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1128\/iai.11.4.649-655.1975"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1128\/iai.16.3.967-973.1977"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.45.11.3070-3075.2001"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00296-10"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-1033.1981.tb05620.x"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2958.2003.03719.x"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.2000.2277"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1099\/mic.0.26426-0"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro2333"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.44.8.2086-2092.2000"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1128\/jb.175.17.5690-5696.1993"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro2474"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.49.8.3114-3121.2005"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/ja.2013.100"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.261483798"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.68.4.2301-2308.2000"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01618-13"},{"key":"e_1_3_2_30_2","volume-title":"Performance standards for antimicrobial susceptibility testing","author":"CLSI","year":"2006","unstructured":"CLSI. 2006. 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