{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T14:15:08Z","timestamp":1769177708315,"version":"3.49.0"},"reference-count":50,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2012,5,22]],"date-time":"2012-05-22T00:00:00Z","timestamp":1337644800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Marine Drugs"],"abstract":"<jats:p>Drug-resistant Staphylococcus aureus is a continuing public health concern, both in the hospital and community settings. Antibacterial compounds that possess novel structural scaffolds and are effective against multiple S. aureus strains, including current drug-resistant ones, are needed. Previously, we have described the chrysophaentins, a family of bisdiarylbutene macrocycles from the chrysophyte alga Chrysophaeum taylori that inhibit the growth of S. aureus and methicillin-resistant S. aureus (MRSA). In this study we have analyzed the geographic variability of chrysophaentin production in C. taylori located at different sites on the island of St. John, U.S. Virgin Islands, and identified two new linear chrysophaentin analogs, E2 and E3. In addition, we have expanded the structure activity relationship through synthesis of fragments comprising conserved portions of the chrysophaentins, and determined the antimicrobial activity of natural chrysophaentins and their synthetic analogs against five diverse S. aureus strains. We find that the chrysophaentins show similar activity against all S. aureus strains, regardless of their drug sensitivity profiles. The synthetic chrysophaentin fragments indeed mimic the natural compounds in their spectrum of antibacterial activity, and therefore represent logical starting points for future medicinal chemistry studies of the natural products and their analogs.<\/jats:p>","DOI":"10.3390\/md10051103","type":"journal-article","created":{"date-parts":[[2012,5,22]],"date-time":"2012-05-22T14:22:46Z","timestamp":1337696566000},"page":"1103-1125","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Geographic Variability and Anti-Staphylococcal Activity of the Chrysophaentins and Their Synthetic Fragments"],"prefix":"10.3390","volume":"10","author":[{"given":"Jessica L.","family":"Keffer","sequence":"first","affiliation":[{"name":"Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jared T.","family":"Hammill","sequence":"additional","affiliation":[{"name":"Center for Chemical Methodologies and Library Development, University of Pittsburgh, Pittsburgh, PA 15260, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John R.","family":"Lloyd","sequence":"additional","affiliation":[{"name":"Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alberto","family":"Plaza","sequence":"additional","affiliation":[{"name":"Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Wipf","sequence":"additional","affiliation":[{"name":"Center for Chemical Methodologies and Library Development, University of Pittsburgh, Pittsburgh, PA 15260, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carole A.","family":"Bewley","sequence":"additional","affiliation":[{"name":"Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2012,5,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S114","DOI":"10.1086\/320184","article-title":"Survey of infections due to Staphylococcus species: Frequency of occurrence and antimicrobial susceptibility of isolates collected in the United States, Canada, Latin America, Europe, and the Western Pacific region for the SENTRY Antimicrobial Surveillance Program, 1997\u20131999","volume":"32","author":"Diekema","year":"2001","journal-title":"Clin. Infect. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1126\/science.99.2579.452","article-title":"Extraction of a highly potent penicillin inactivator from penicillin resistant Staphylococci","volume":"99","author":"Kirby","year":"1944","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1016\/S0140-6736(48)92166-7","article-title":"Infection by penicillin-resistant staphylococci","volume":"2","author":"Barber","year":"1948","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1136\/bmj.1.5219.124-a","article-title":"\u201cCelbenin\u201d-resistant Staphylococci","volume":"1","author":"Jevons","year":"1961","journal-title":"Br. Med. J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1136\/bmj.1.5326.308","article-title":"Evolution of natural resistance to the newer penicillins","volume":"1","author":"Stewart","year":"1963","journal-title":"Br. Med. J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1089\/mdr.1998.4.107","article-title":"Spread of the multiresistant Iberian clone of methicillin-resistant Staphylococcus aureus (MRSA) to Italy and Scotland","volume":"4","author":"Mato","year":"1998","journal-title":"Microb. Drug Resist."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1763","DOI":"10.1001\/jama.298.15.1763","article-title":"Invasive methicillin-resistant Staphylococcus aureus infections in the United States","volume":"298","author":"Klevens","year":"2007","journal-title":"J. Am. Med. Assoc."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1016\/j.diagmicrobio.2010.03.006","article-title":"Methicillin-resistant Staphylococcus aureus resistance to non-beta-lactam antimicrobials in the United States from 1996 to 2008","volume":"67","author":"Bordon","year":"2010","journal-title":"Diagn. Microbiol. Infect. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1056\/NEJMoa055356","article-title":"Methicillin-resistant S. aureus infections among patients in the emergency department","volume":"355","author":"Moran","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1086\/526773","article-title":"Clinical practice: Colonization, fomites, and virulence: Rethinking the pathogenesis of community-associated methicillin-resistant Staphylococcus aureus infection","volume":"46","author":"Miller","year":"2008","journal-title":"Clin. Infect. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1819","DOI":"10.1016\/S0140-6736(02)08713-5","article-title":"Genome and virulence determinants of high virulence community-acquired MRSA","volume":"359","author":"Baba","year":"2002","journal-title":"Lancet"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1344","DOI":"10.1086\/344326","article-title":"A novel methicillin-resistance cassette in community-acquired methicillin-resistant Staphylococcus aureus isolates of diverse genetic backgrounds","volume":"186","author":"Daum","year":"2002","journal-title":"J. Infect. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4289","DOI":"10.1128\/JCM.40.11.4289-4294.2002","article-title":"Dissemination of new methicillin-resistant Staphylococcus aureus clones in the community","volume":"40","author":"Okuma","year":"2002","journal-title":"J. Clin. Microbiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"978","DOI":"10.3201\/eid0908.030089","article-title":"Community-acquired methicillin-resistant Staphylococcus aureus carrying Panton-Valentine leukocidin genes: Worldwide emergence","volume":"9","author":"Vandenesch","year":"2003","journal-title":"Emerg. Infect. Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.1086\/313461","article-title":"Involvement of Panton-Valentine leukocidin-producing Staphylococcus aureus in primary skin infections and pneumonia","volume":"29","author":"Lina","year":"1999","journal-title":"Clin. Infect. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1056\/NEJMcpc1003886","article-title":"Case records of the Massachusetts General Hospital. Case 2\u20132011. A 30-year-old woman with shock after treatment of a furuncle","volume":"364","author":"Moellering","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1557","DOI":"10.1016\/S0140-6736(09)61999-1","article-title":"Community-associated meticillin-resistant Staphylococcus aureus","volume":"375","author":"Deleo","year":"2010","journal-title":"Lancet"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1086\/313706","article-title":"Clonal features of community-acquired methicillin-resistant Staphylococcus aureus in children","volume":"30","author":"Frank","year":"2000","journal-title":"Clin. Infect. Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1128\/JCM.44.1.108-118.2006","article-title":"Characterization of a strain of community-associated methicillin-resistant Staphylococcus aureus widely disseminated in the United States","volume":"44","author":"Tenover","year":"2006","journal-title":"J. Clin. Microbiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1086\/587907","article-title":"The arginine catabolic mobile element and staphylococcal chromosomal cassette mec linkage: Convergence of virulence and resistance in the USA300 clone of methicillin-resistant Staphylococcus aureus","volume":"197","author":"Diep","year":"2008","journal-title":"J. Infect. Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1086\/523767","article-title":"Understanding the success of methicillin-resistant Staphylococcus aureus strains causing epidemic disease in the community","volume":"197","author":"Gorwitz","year":"2008","journal-title":"J. Infect. Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1086\/590157","article-title":"Comparison of virulence in community-associated methicillin-resistant Staphylococcus aureus pulsotypes USA300 and USA400 in a rat model of pneumonia","volume":"198","author":"Montgomery","year":"2008","journal-title":"J. Infect. Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1038\/nrd2201","article-title":"Drugs for bad bugs: Confronting the challenges of antibacterial discovery","volume":"6","author":"Payne","year":"2007","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1021\/np200906s","article-title":"Natural products as sources of new drugs over the 30 years from 1981 to 2010","volume":"75","author":"Newman","year":"2012","journal-title":"J. Nat. Prod."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1016\/j.ijantimicag.2007.07.011","article-title":"Reduced glycopeptide susceptibility in methicillin-resistant Staphylococcus aureus (MRSA)","volume":"30","author":"Appelbaum","year":"2007","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/S1473-3099(05)70112-2","article-title":"Community-acquired meticillin-resistant Staphylococcus aureus: An emerging threat","volume":"5","author":"Zetola","year":"2005","journal-title":"Lancet Infect. Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"9069","DOI":"10.1021\/ja102100h","article-title":"Chrysophaentins A\u2013H, antibacterial bisdiarylbutene macrocycles that inhibit the bacterial cell division protein FtsZ","volume":"132","author":"Plaza","year":"2010","journal-title":"J. Am. Chem. Soc."},{"key":"ref_28","unstructured":"Image: U.S. Geological Survey, Image copyright: 2012 Digital Globe, GeoEye, Google."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1002\/adsc.200600570","article-title":"Asymmetric total synthesis of nigerone and ent-nigerone: Enantioselective oxidative biaryl coupling of highly hindered naphthols","volume":"349","author":"Kozlowski","year":"2007","journal-title":"Adv. Synth. Catal."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"13936","DOI":"10.1021\/ja0454236","article-title":"A new convergent strategy for the synthesis of calixarenes via a triple annulation of Fischer carbene complexes","volume":"126","author":"Gopalsamuthiram","year":"2004","journal-title":"J. Am. Chem. Soc."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"10175","DOI":"10.1021\/jo035372f","article-title":"Reaction of alkynes with iodine monochloride revisited","volume":"68","author":"Bellina","year":"2003","journal-title":"J. Org. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1039\/p19770000676","article-title":"Chlorination and chloroiodination of acetylenes with copper(II) chloride","volume":"6","author":"Uemura","year":"1977","journal-title":"J. Chem. Soc. Perkin Trans. 1"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"16786","DOI":"10.1021\/ja805936v","article-title":"Synthesis of pluraflavin A \u201caglycone\u201d","volume":"130","author":"Wright","year":"2008","journal-title":"J. Am. Chem. Soc."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"7906","DOI":"10.1021\/jo00079a042","article-title":"Preparation of functionalized juglone acetates and juglones via 1,4-dimethoxynaphthalene derivatives: Synthesis of anthraquinones related to rhein and aloe emodin","volume":"58","author":"Bloomer","year":"1993","journal-title":"J. Org. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1016\/j.tet.2007.11.031","article-title":"Negishi cross-coupling reactions of alpha-amino acid-derived organozinc reagents and aromatic bromides","volume":"64","author":"Oswald","year":"2008","journal-title":"Tetrahedron"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1128\/jcm.33.5.1243-1246.1995","article-title":"Evidence for the geographic spread of a methicillin-resistant Staphylococcus aureus clone between Portugal and Spain","volume":"33","author":"Sanches","year":"1995","journal-title":"J. Clin. Microbiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3373","DOI":"10.1128\/iai.63.9.3373-3380.1995","article-title":"Role of the accessory gene regulator (agr) in pathogenesis of staphylococcal osteomyelitis","volume":"63","author":"Gillaspy","year":"1995","journal-title":"Infect. Immun."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"5113","DOI":"10.1128\/JCM.41.11.5113-5120.2003","article-title":"Pulsed-field gel electrophoresis typing of oxacillin-resistant Staphylococcus aureus isolates from the United States: Establishing a national database","volume":"41","author":"McDougal","year":"2003","journal-title":"J. Clin. Microbiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1172","DOI":"10.1111\/j.1462-5822.2006.00858.x","article-title":"Global analysis of community-associated methicillin-resistant Staphylococcus aureus exoproteins reveals molecules produced in vitro and during infection","volume":"9","author":"Burlak","year":"2007","journal-title":"Cell Microbiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1002\/j.1537-2197.1941.tb07978.x","article-title":"A new protophyte from the Dry Tortugas","volume":"28","author":"Bryan","year":"1941","journal-title":"Am. J. Bot."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1979","DOI":"10.1016\/S0040-4039(00)84426-3","article-title":"Hormothamnione, a novel cytotoxic styrylchromone from the marine cyanophyte Hormothamnion enteromorphoides grunow","volume":"27","author":"Gerwick","year":"1986","journal-title":"Tetrahedron Lett."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1021\/np50062a005","article-title":"6-Desmethoxyhormothamnione, a new cytotoxic styrylchromone from the marine cryptophyte Chrysophaeum taylori","volume":"52","author":"Gerwick","year":"1989","journal-title":"J. Nat. Prod."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1039\/C1NP00080B","article-title":"Macrocylic bisbibenzyl natural products and their chemical synthesis","volume":"29","author":"Harrowven","year":"2012","journal-title":"Nat. Prod. Rep."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1016\/S0031-9422(00)84025-X","article-title":"Distribution of novel cyclic bisbibenzyls in Marchantia and Riccardia species","volume":"22","author":"Asakawa","year":"1983","journal-title":"Phytochemistry"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1016\/S0031-9422(03)00382-0","article-title":"Bazzanins L-R, chlorinated macrocyclic bisbibenzyls from the liverwort Lepidozia incurvata","volume":"64","author":"Scher","year":"2003","journal-title":"Phytochemistry"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1016\/S0031-9422(97)01076-5","article-title":"Lignans from the liverwort Bazzania trilobata","volume":"49","author":"Martini","year":"1998","journal-title":"Phytochemistry"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3153","DOI":"10.1016\/S0040-4020(00)00236-2","article-title":"New chlorinated cyclic bis(bibenzyls) from the liverworts Herbertus sakuraii and Mastigophora diclados","volume":"56","author":"Hashimoto","year":"2000","journal-title":"Tetrahedron"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1016\/S0031-9422(98)00557-3","article-title":"Biosynthesis of cyclic bis(bibenzyls) in Marchantia polymorpha","volume":"50","author":"Friederich","year":"1999","journal-title":"Phytochemistry"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.ab.2008.09.026","article-title":"Top-down N-terminal sequencing of immunoglobulin subunits with electrospray ionization time of flight mass spectrometry","volume":"384","author":"Ren","year":"2009","journal-title":"Anal.Biochem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1016\/S0040-4039(00)72715-8","article-title":"An efficient route to 3-chlorojuglones","volume":"30","author":"Bloomer","year":"1989","journal-title":"Tetrahedron Lett."}],"container-title":["Marine Drugs"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-3397\/10\/5\/1103\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:50:24Z","timestamp":1760219424000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-3397\/10\/5\/1103"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,5,22]]},"references-count":50,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2012,5]]}},"alternative-id":["md10051103"],"URL":"https:\/\/doi.org\/10.3390\/md10051103","relation":{},"ISSN":["1660-3397"],"issn-type":[{"value":"1660-3397","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,5,22]]}}}