{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T00:15:04Z","timestamp":1790381704982,"version":"4.1.0"},"reference-count":24,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2021,8,27]],"date-time":"2021-08-27T00:00:00Z","timestamp":1630022400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Australian National Health and Medical Research Council","award":["1071659"],"award-info":[{"award-number":["1071659"]}]},{"name":"Principal Research Fellowship","award":["1138466"],"award-info":[{"award-number":["1138466"]}]},{"name":"Development Grant","award":["1176180"],"award-info":[{"award-number":["1176180"]}]},{"name":"Investigator Grant","award":["1196520"],"award-info":[{"award-number":["1196520"]}]},{"name":"Investigator Grant","award":["1194130"],"award-info":[{"award-number":["1194130"]}]},{"name":"Ideas Grant","award":["2001210"],"award-info":[{"award-number":["2001210"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,10,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Neisseria gonorrhoeae is a Gram-negative bacterial pathogen that causes gonorrhoea. No vaccine is available to prevent gonorrhoea and the emergence of MDR N. gonorrhoeae strains represents an immediate public health threat.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>To evaluate whether PBT2\/zinc may sensitize MDR N. gonorrhoeae to natural cationic antimicrobial peptides.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>MDR strains that contain differing resistance mechanisms against numerous antibiotics were tested in MIC assays. MIC assays were performed using the broth microdilution method according to CLSI guidelines in a microtitre plate. Serially diluted LL-37 or PG-1 was tested in combination with a sub-inhibitory concentration of PBT2\/zinc. Serially diluted tetracycline was also tested with sub-inhibitory concentrations of PBT2\/zinc and LL-37. SWATH-MS proteomic analysis of N. gonorrhoeae treated with PBT2\/zinc, LL-37 and\/or tetracycline was performed to determine the mechanism(s) of N. gonorrhoeae susceptibility to antibiotics and peptides.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Sub-inhibitory concentrations of LL-37 and PBT2\/zinc synergized to render strain WHO-Z susceptible to tetracycline, whereas the killing effect of PG-1 and PBT2\/zinc was additive. SWATH-MS proteomic analysis suggested that PBT2\/zinc most likely leads to a loss of membrane integrity and increased protein misfolding and, in turn, results in bacterial death.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Here we show that PBT2, a candidate Alzheimer\u2019s and Huntington\u2019s disease drug, can be repurposed to render MDR N. gonorrhoeae more susceptible to the endogenous antimicrobial peptides LL-37 and PG-1. In the presence of LL-37, PBT2\/zinc can synergize with tetracycline to restore tetracycline susceptibility to gonococci resistant to this antibiotic.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/jac\/dkab291","type":"journal-article","created":{"date-parts":[[2021,8,27]],"date-time":"2021-08-27T22:42:11Z","timestamp":1630104131000},"page":"2850-2853","source":"Crossref","is-referenced-by-count":12,"title":["A drug candidate for Alzheimer\u2019s and Huntington\u2019s disease, PBT2, can be repurposed to render <i>Neisseria gonorrhoeae<\/i> susceptible to natural cationic antimicrobial peptides"],"prefix":"10.1093","volume":"76","author":[{"given":"Freda E -C","family":"Jen","sequence":"first","affiliation":[{"name":"Institute for Glycomics, Griffith University, Gold Coast Campus, Southport, Queensland 4222, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ibrahim M","family":"El-Deeb","sequence":"additional","affiliation":[{"name":"Institute for Glycomics, Griffith University, Gold Coast Campus, Southport, Queensland 4222, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaramah M","family":"Zalucki","sequence":"additional","affiliation":[{"name":"Institute for Glycomics, Griffith University, Gold Coast Campus, Southport, Queensland 4222, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer L","family":"Edwards","sequence":"additional","affiliation":[{"name":"The Center for Microbial Pathogenesis, The Abigail Wexner Research Institute at Nationwide Children's Hospital and The Department of Pediatrics, The Ohio State University, Columbus, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark J","family":"Walker","sequence":"additional","affiliation":[{"name":"School of Chemistry and Molecular Biosciences and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Queensland, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"von Itzstein","sequence":"additional","affiliation":[{"name":"Institute for Glycomics, Griffith University, Gold Coast Campus, Southport, Queensland 4222, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael P","family":"Jennings","sequence":"additional","affiliation":[{"name":"Institute for Glycomics, Griffith University, Gold Coast Campus, Southport, Queensland 4222, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,8,27]]},"reference":[{"key":"2021101808551757000_dkab291-B1","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1038\/s41572-019-0128-6","article-title":"Gonorrhoea","volume":"5","author":"Unemo","year":"2019","journal-title":"Nat Rev Dis Primers"},{"key":"2021101808551757000_dkab291-B2","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1016\/S0091-7435(02)00058-0","article-title":"Asymptomatic sexually transmitted diseases: the case for screening","volume":"36","author":"Farley","year":"2003","journal-title":"Prev Med"},{"key":"2021101808551757000_dkab291-B3","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1097\/OLQ.0000000000000602","article-title":"Retrospective review of gonococcal and chlamydial cases of epididymitis at 2 Canadian sexually transmitted infection clinics, 2004-2014","volume":"44","author":"Chen","year":"2017","journal-title":"Sex Transm Dis"},{"key":"2021101808551757000_dkab291-B4","doi-asserted-by":"crossref","first-page":"928","DOI":"10.3109\/1040841X.2015.1105782","article-title":"Is gonococcal disease preventable? The importance of understanding immunity and pathogenesis in vaccine development","volume":"42","author":"Edwards","year":"2016","journal-title":"Crit Rev Microbiol"},{"key":"2021101808551757000_dkab291-B5","doi-asserted-by":"crossref","first-page":"3096","DOI":"10.1093\/jac\/dkw288","article-title":"The novel 2016 WHO Neisseria gonorrhoeae reference strains for global quality assurance of laboratory investigations: phenotypic, genetic and reference genome characterization","volume":"71","author":"Unemo","year":"2016","journal-title":"J Antimicrob Chemother"},{"key":"2021101808551757000_dkab291-B6","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1016\/S1474-4422(08)70167-4","article-title":"Safety, efficacy, and biomarker findings of PBT2 in targeting A\u03b2 as a modifying therapy for Alzheimer's disease: a phase IIa, double-blind, randomised, placebo-controlled trial","volume":"7","author":"Lannfelt","year":"2008","journal-title":"Lancet Neurol"},{"key":"2021101808551757000_dkab291-B7","doi-asserted-by":"crossref","first-page":"e02391-18","DOI":"10.1128\/mBio.02391-18","article-title":"Chemical synergy between ionophore PBT2 and zinc reverses antibiotic resistance","volume":"9","author":"Bohlmann","year":"2018","journal-title":"MBio"},{"key":"2021101808551757000_dkab291-B8","doi-asserted-by":"crossref","first-page":"1922","DOI":"10.3389\/fmicb.2018.01922","article-title":"Structure-function relationships of the neisserial EptA enzyme responsible for phosphoethanolamine decoration of lipid A: rationale for drug targeting","volume":"9","author":"Kahler","year":"2018","journal-title":"Front Microbiol"},{"key":"2021101808551757000_dkab291-B9","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1021\/acsinfecdis.9b00307","article-title":"Neisseria gonorrhoeae becomes susceptible to polymyxin B and colistin in the presence of PBT2","volume":"6","author":"Jen","year":"2020","journal-title":"ACS Infect Dis"},{"key":"2021101808551757000_dkab291-B10","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1093\/cid\/ciu213","article-title":"Colistin and polymyxin B: peas in a pod, or chalk and cheese?","volume":"59","author":"Nation","year":"2014","journal-title":"Clin Infect Dis"},{"key":"2021101808551757000_dkab291-B11","doi-asserted-by":"crossref","first-page":"5387","DOI":"10.1128\/JB.187.15.5387-5396.2005","article-title":"Cationic antimicrobial peptide resistance in Neisseria meningitidis","volume":"187","author":"Tzeng","year":"2005","journal-title":"J Bacteriol"},{"key":"2021101808551757000_dkab291-B12","doi-asserted-by":"crossref","first-page":"eabb3791","DOI":"10.1126\/scitranslmed.abb3791","article-title":"Repurposing a neurodegenerative disease drug to treat Gram-negative antibiotic-resistant bacterial sepsis","volume":"12","author":"De Oliveira","year":"2020","journal-title":"Sci Transl Med"},{"key":"2021101808551757000_dkab291-B13","doi-asserted-by":"crossref","first-page":"2356","DOI":"10.1021\/acs.jproteome.5b00938","article-title":"Neisseria meningitidis lacking the major porins PorA and PorB is viable and modulates apoptosis and the oxidative burst of neutrophils","volume":"15","author":"Peak","year":"2016","journal-title":"J Proteome Res"},{"key":"2021101808551757000_dkab291-B14","doi-asserted-by":"crossref","first-page":"5354","DOI":"10.1128\/IAI.68.9.5354-5363.2000","article-title":"Neisseria gonorrhoeae elicits membrane ruffling and cytoskeletal rearrangements upon infection of primary human endocervical and ectocervical cells","volume":"68","author":"Edwards","year":"2000","journal-title":"Infect Immun"},{"key":"2021101808551757000_dkab291-B15","doi-asserted-by":"crossref","first-page":"1408","DOI":"10.1016\/j.bbamem.2006.03.030","article-title":"LL-37, the only human member of the cathelicidin family of antimicrobial peptides","volume":"1758","author":"Durr","year":"2006","journal-title":"Biochim Biophys Acta"},{"key":"2021101808551757000_dkab291-B16","doi-asserted-by":"crossref","first-page":"13","DOI":"10.3390\/ph9010013","article-title":"Potential use of antimicrobial peptides as vaginal spermicides\/microbicides","volume":"9","author":"Tanphaichitr","year":"2016","journal-title":"Pharmaceuticals (Basel)"},{"key":"2021101808551757000_dkab291-B17","doi-asserted-by":"crossref","first-page":"3245","DOI":"10.1093\/jac\/dkz339","article-title":"Cationic cell-penetrating peptide is bactericidal against Neisseria gonorrhoeae","volume":"74","author":"John","year":"2019","journal-title":"J Antimicrob Chemother"},{"key":"2021101808551757000_dkab291-B18","doi-asserted-by":"crossref","first-page":"1664","DOI":"10.1128\/IAI.68.3.1664-1671.2000","article-title":"Bacterial phosphorylcholine decreases susceptibility to the antimicrobial peptide LL-37\/hCAP18 expressed in the upper respiratory tract","volume":"68","author":"Lysenko","year":"2000","journal-title":"Infect Immun"},{"key":"2021101808551757000_dkab291-B19","doi-asserted-by":"crossref","first-page":"1738","DOI":"10.1128\/AAC.41.8.1738","article-title":"Protegrin-1: a broad-spectrum, rapidly microbicidal peptide with in vivo activity","volume":"41","author":"Steinberg","year":"1997","journal-title":"Antimicrob Agents Chemother"},{"key":"2021101808551757000_dkab291-B20","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1016\/0923-2508(94)90083-3","article-title":"Signal transduction by the EnvZ-OmpR phosphotransfer system in bacteria","volume":"145","author":"Forst","year":"1994","journal-title":"Res Microbiol"},{"key":"2021101808551757000_dkab291-B21","doi-asserted-by":"crossref","first-page":"9009","DOI":"10.1073\/pnas.160261497","article-title":"The cysteine desulfurase, IscS, has a major role in in vivo Fe-S cluster formation in Escherichia coli","volume":"97","author":"Schwartz","year":"2000","journal-title":"Proc Natl Acad Sci USA"},{"key":"2021101808551757000_dkab291-B22","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1111\/j.1365-2958.2006.05478.x","article-title":"Characterization of the OxyR regulon of Neisseria gonorrhoeae","volume":"63","author":"Seib","year":"2007","journal-title":"Mol Microbiol"},{"key":"2021101808551757000_dkab291-B23","doi-asserted-by":"crossref","DOI":"10.1128\/ecosalplus.ESP-0005-2018","article-title":"Periplasmic chaperones and prolyl isomerases","volume":"8","author":"Stull","year":"2018","journal-title":"EcoSal Plus"},{"key":"2021101808551757000_dkab291-B24","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/S1474-4422(14)70262-5","article-title":"Safety, tolerability, and efficacy of PBT2 in Huntington's disease: a phase 2, randomised, double-blind, placebo-controlled trial","volume":"14","year":"2015","journal-title":"Lancet Neurol"}],"container-title":["Journal of Antimicrobial Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/jac\/article-pdf\/76\/11\/2850\/40641263\/dkab291.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/jac\/article-pdf\/76\/11\/2850\/40641263\/dkab291.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,10,20]],"date-time":"2021-10-20T20:25:39Z","timestamp":1634761539000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jac\/article\/76\/11\/2850\/6358702"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,27]]},"references-count":24,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,8,27]]},"published-print":{"date-parts":[[2021,10,11]]}},"URL":"https:\/\/doi.org\/10.1093\/jac\/dkab291","relation":{},"ISSN":["0305-7453","1460-2091"],"issn-type":[{"value":"0305-7453","type":"print"},{"value":"1460-2091","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,11,1]]},"published":{"date-parts":[[2021,8,27]]}}}