{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T17:12:51Z","timestamp":1789924371227,"version":"4.0.1"},"reference-count":57,"publisher":"National Academy of Sciences","issue":"19","license":[{"start":{"date-parts":[[2019,4,19]],"date-time":"2019-04-19T00:00:00Z","timestamp":1555632000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["AI-26289"],"award-info":[{"award-number":["AI-26289"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2019,5,7]]},"abstract":"<jats:title>Significance<\/jats:title>\n                  <jats:p>This paper demonstrates that aminoglycoside antibiotics induce the production of the Ap4A in bacteria. Increased intracellular Ap4A, in turn, promotes bacterial cell killing by this class of antibiotics, which correlated well with elevated damage to the bacterial membrane upon aminoglycoside treatment. These findings reveal a striking connection between aminoglycoside killing and the Ap4A production particularly under conditions of oxidative stress. Importantly, the results of this study suggest that targeting Ap4A degradation or inducing its hypersynthesis during therapy with aminoglycosides might help solve the well-known toxicity issue associated with this class of antibiotics by reducing the level of drug needed for effective treatment.<\/jats:p>","DOI":"10.1073\/pnas.1822026116","type":"journal-article","created":{"date-parts":[[2019,4,19]],"date-time":"2019-04-19T20:35:27Z","timestamp":1555706127000},"page":"9578-9585","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":66,"title":["Alarmone Ap4A is elevated by aminoglycoside antibiotics and enhances their bactericidal activity"],"prefix":"10.1073","volume":"116","author":[{"given":"Xia","family":"Ji","sequence":"first","affiliation":[{"name":"Faculty of Health Sciences, University of Macau, Macau SAR, China;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Zou","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences, University of Macau, Macau SAR, China;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haibo","family":"Peng","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences, University of Macau, Macau SAR, China;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne-Sophie","family":"Stolle","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruiqiang","family":"Xie","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences, University of Macau, Macau SAR, China;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongjie","family":"Zhang","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences, University of Macau, Macau SAR, China;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5698-6097","authenticated-orcid":false,"given":"Bo","family":"Peng","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Sun Yat-sen University, Guangzhou 510006, China;"},{"name":"Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266071, China;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John J.","family":"Mekalanos","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Zheng","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences, University of Macau, Macau SAR, China;"},{"name":"Institute of Translational Medicine, University of Macau, Macau SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2019,4,19]]},"reference":[{"key":"e_1_3_3_1_2","unstructured":"J O\u2019Neill Antimicrobial Resistance: Tackling a crisis for the health and wealth of nations The Review on Antimicrobial Resistance .  (HM Government London 2014)."},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.2165\/11597020-000000000-00000"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/mr.51.3.341-350.1987"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.83.16.6164"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2008.09.038"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.06.049"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1401876111"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.100422497"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature10317"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2014.12.008"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2012.10.001"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1159\/000058305"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.43.5.1003"},{"key":"e_1_3_3_14_2","first-page":"235","volume-title":"The Aminoglycosides: Microbiology, Clinical Use and Toxi- Cology","author":"Parker RA","year":"1982","unstructured":"RA Parker, WH Bennett, GA Porter, Animal models in the study of aminoglycoside nephrotoxicity. The Aminoglycosides: Microbiology, Clinical Use and Toxi- Cology, eds A Whelton, HC Neu (Marcel Dekker, Inc., New York), pp. 235\u2013267 (1982)."},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1093\/dnares\/dsu032"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/0006-291X(66)90416-5"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(84)90318-0"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj2480043"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.86.13.5010"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(04)00020-2"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2009.05.019"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2017.81"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.08.014"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1801233115"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-0953-5"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.06.026"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchromb.2014.05.018"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)68927-1"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.2834821"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1111\/febs.12053"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.420380"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41426-018-0038-9"},{"key":"e_1_3_3_33_2","unstructured":"; World Health Organization WHO publishes list of bacteria for which new antibiotics are urgently needed. Available at www.who.int\/mediacentre\/news\/releases\/2017\/bacteria-antibiotics-needed\/en\/ Accessed April 6 2019. (2017)."},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.02577-14"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro.2016.190"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aat1022"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1991.tb04959.x"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00853-18"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00144-08"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1226683"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.1141"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1111\/febs.14113"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1021\/cr0301088"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2993"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2018.01.004"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2018.10.022"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1128\/jb.175.8.2321-2326.1993"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2014.04.076"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2011.09.070"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00315-10"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.01655-17"},{"key":"e_1_3_3_52_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.73.7.4127-4137.2005"},{"key":"e_1_3_3_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.plasmid.2004.02.003"},{"key":"e_1_3_3_54_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0503005102"},{"key":"e_1_3_3_55_2","doi-asserted-by":"publisher","DOI":"10.1128\/jb.177.14.4121-4130.1995"},{"key":"e_1_3_3_56_2","doi-asserted-by":"publisher","DOI":"10.1128\/9781555817381.ch71"},{"key":"e_1_3_3_57_2","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.M002923"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.pnas.org\/syndication\/doi\/10.1073\/pnas.1822026116","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.1822026116","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,13]],"date-time":"2022-04-13T05:16:29Z","timestamp":1649826989000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.1822026116"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,4,19]]},"references-count":57,"journal-issue":{"issue":"19","published-print":{"date-parts":[[2019,5,7]]}},"alternative-id":["10.1073\/pnas.1822026116"],"URL":"https:\/\/doi.org\/10.1073\/pnas.1822026116","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,4,19]]},"assertion":[{"value":"2019-04-19","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}