{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,4]],"date-time":"2025-10-04T01:24:26Z","timestamp":1759541066896,"version":"3.37.3"},"reference-count":38,"publisher":"Portland Press Ltd.","issue":"5","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2019,3,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Antibiotic-resistant bacteria pose the greatest threat to human health. Among the list of such bacteria released by WHO, carbapenem-resistant Acinetobacter baumannii, for which almost no treatment exists, tops the list. A. baumannii is one of the most troublesome ESKAPE pathogens and mechanisms that have facilitated its rise as a successful pathogen are not well studied. Efforts in this direction have resulted in the identification of Hpa2-Ab, an uncharacterized histone acetyltransferase enzyme of GNAT superfamily. Here, we show that Hpa2-Ab confers resistance against aminoglycoside antibiotics using Escherichia coli DH5\u03b1 strains in which Hpa2 gene is expressed. Resistivity for aminoglycoside antibiotics is demonstrated with the help of CLSI-2010 and KB tests. Isothermal titration calorimetry, MALDI and acetylation assays indicate that conferred resistance is an outcome of evolved antibiotic acetylation capacity in this. Hpa2 is known to acetylate nuclear molecules; however, here it is found to cross its boundary and participate in other functions. An array of biochemical and biophysical techniques were also used to study this protein, which demonstrates that Hpa2-Ab is intrinsically oligomeric in nature, exists primarily as a dimer and its interface is mainly stabilized by hydrophobic interactions. Our work demonstrates an evolved survival strategy by A. baumannii and provides insights into the mechanism that facilitates it to rise as a successful pathogen.<\/jats:p>","DOI":"10.1042\/bcj20180791","type":"journal-article","created":{"date-parts":[[2018,12,20]],"date-time":"2018-12-20T21:35:17Z","timestamp":1545341717000},"page":"795-808","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Aminoglycoside antibiotic resistance conferred by Hpa2 of MDR <i>Acinetobacter baumannii<\/i>: an unusual adaptation of a common histone acetyltransferase"],"prefix":"10.1042","volume":"476","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9708-6370","authenticated-orcid":false,"given":"Jyoti Singh","family":"Tomar","sequence":"first","affiliation":[{"name":"Department of Chemical Sciences, Tata Institute of Fundamental Research, Mumbai 400005, Maharashtra, India"},{"name":"Department of Chemistry, Indian Institute of Technology Roorkee, Roorkee 247667, Uttarakhand, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rama Krishna","family":"Peddinti","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Indian Institute of Technology Roorkee, Roorkee 247667, Uttarakhand, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ramakrishna V.","family":"Hosur","sequence":"additional","affiliation":[{"name":"Department of Chemical Sciences, Tata Institute of Fundamental Research, Mumbai 400005, Maharashtra, India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"288","published-online":{"date-parts":[[2019,3,6]]},"reference":[{"key":"2021112217562941300_BCJ-2018-0791C1","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1128\/MMBR.00016-10","article-title":"Origins and evolution of antibiotic resistance","volume":"74","year":"2010","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"2021112217562941300_BCJ-2018-0791C2","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1038\/nrmicro.2017.28","article-title":"Next-generation approaches to understand and combat the antibiotic resistome","volume":"15","year":"2017","journal-title":"Nat. Rev. Microbiol."},{"key":"2021112217562941300_BCJ-2018-0791C3","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1038\/nrg3922","article-title":"Evolutionary consequences of drug resistance: shared principles across diverse targets and organisms","volume":"16","year":"2015","journal-title":"Nat. Rev. Genet."},{"key":"2021112217562941300_BCJ-2018-0791C4","doi-asserted-by":"publisher","first-page":"689","DOI":"10.1038\/nrmicro.2017.75","article-title":"Prediction of antibiotic resistance: time for a new paradigm?","volume":"15","year":"2017","journal-title":"Nat. Rev. Microbiol."},{"key":"2021112217562941300_BCJ-2018-0791C5","doi-asserted-by":"publisher","first-page":"1332","DOI":"10.1097\/CCM.0000000000001029","article-title":"Combination therapy for extreme drug resistant (XDR) Acinetobacter baumannii: ready for Prime-Time?","volume":"43","year":"2015","journal-title":"Crit. Care Med."},{"key":"2021112217562941300_BCJ-2018-0791C6","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1086\/653120","article-title":"Treatment of Acinetobacter infections","volume":"51","year":"2010","journal-title":"Clin. Infect. Dis."},{"key":"2021112217562941300_BCJ-2018-0791C7","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1128\/mr.57.1.138-163.1993","article-title":"Molecular genetics of aminoglycoside resistance genes and familial relationships of the aminoglycoside-modifying enzymes","volume":"57","year":"1993","journal-title":"Microbiol. Rev."},{"key":"2021112217562941300_BCJ-2018-0791C8","doi-asserted-by":"publisher","first-page":"1103","DOI":"10.20546\/ijcmas.2017.611.130","article-title":"Aminoglycosides resistance among Acinetobacter baumannii complex isolated from hospital acquired blood stream infections","volume":"6","year":"2017","journal-title":"Int. J. Curr. Microbiol Appl. Sci."},{"key":"2021112217562941300_BCJ-2018-0791C9","doi-asserted-by":"publisher","first-page":"1115","DOI":"10.1080\/07391102.2016.1172025","article-title":"A. baumannii histone acetyl-transferases Hpa2: optimization of homology modeling, analysis of protein\u2013protein interaction and virtual screening","volume":"35","year":"2017","journal-title":"J. Biomol. Struct. Dyn."},{"key":"2021112217562941300_BCJ-2018-0791C10","doi-asserted-by":"publisher","first-page":"1018","DOI":"10.3390\/ijms17071018","article-title":"Structure and functional diversity of GCN5-related N-acetyltransferases (GNAT)","volume":"17","year":"2016","journal-title":"Int. J. Mol. Sci."},{"key":"2021112217562941300_BCJ-2018-0791C11","doi-asserted-by":"publisher","first-page":"21506","DOI":"10.1074\/jbc.M113.486274","article-title":"Acetyltransferases from S. cerevisiae Hpa3-two small closely related biochemical characterization of Hpa2 and enzymology","volume":"288","year":"2013","journal-title":"J. Biol. Chem."},{"key":"2021112217562941300_BCJ-2018-0791C12","doi-asserted-by":"publisher","first-page":"1311","DOI":"10.1006\/jmbi.1999.3338","article-title":"Crystal structure of the histone acetyltransferase Hpa2: a tetrameric member of the Gcn5-related N-acetyltransferase superfamily","volume":"294","year":"1999","journal-title":"J. Mol. Biol."},{"key":"2021112217562941300_BCJ-2018-0791C13","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1128\/mBio.00216-11","article-title":"Biochemical and thermodynamic analyses of Salmonella enterica Pat, a multidomain, multimeric N-Lysine acetyltransferase involved in carbon and energy metabolism","volume":"2","year":"2011","journal-title":"mBio"},{"key":"2021112217562941300_BCJ-2018-0791C14","doi-asserted-by":"publisher","first-page":"426","DOI":"10.1110\/ps.0233503","article-title":"X-ray structure of AAC(6_)-Ii antibiotic resistance enzyme at 1.8\u2005\u00c5 resolution; examination of oligomeric arrangements in GNAT superfamily members","volume":"12","year":"2003","journal-title":"Protein Sci."},{"key":"2021112217562941300_BCJ-2018-0791C15","doi-asserted-by":"publisher","first-page":"3259","DOI":"10.1039\/C6MB00517A","article-title":"Characterization of substrate binding and enzymatic removal of a 3-methyladenine lesion from genomic DNA with TAG of MDR A. baumannii","volume":"12","year":"2016","journal-title":"Mol. BioSyst."},{"key":"2021112217562941300_BCJ-2018-0791C16","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1007\/978-1-4939-6850-3_2","article-title":"DTNB-Based quantification of in vitro enzymatic N-terminal acetyltransferase activity","volume":"1574","year":"2017","journal-title":"Methods Mol. Biol."},{"key":"2021112217562941300_BCJ-2018-0791C17","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1038\/nm1347","article-title":"Fluoroquinolone-modifying enzyme: a new adaptation of a common aminoglycoside acetyltransferase","volume":"12","year":"2006","journal-title":"Nat. Med."},{"volume-title":"Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically, Approved Standard 10th Edition","year":"2015","key":"2021112217562941300_BCJ-2018-0791C18"},{"key":"2021112217562941300_BCJ-2018-0791C19","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1093\/ajcp\/45.4_ts.493","article-title":"Antibiotic susceptibility testing by a standardized single disk method","volume":"45","year":"1966","journal-title":"Am. J. Clin. Pathol."},{"key":"2021112217562941300_BCJ-2018-0791C20","first-page":"1253","volume-title":"Susceptibility Test Methods: Dilution and Disk Diffusion Methods: Manual of Clinical Microbiology","year":"2015","edition":"11th edn"},{"key":"2021112217562941300_BCJ-2018-0791C21","doi-asserted-by":"publisher","first-page":"418","DOI":"10.1038\/nprot.2006.62","article-title":"Blue native PAGE","volume":"1","year":"2006","journal-title":"Nat. Protoc."},{"key":"2021112217562941300_BCJ-2018-0791C22","doi-asserted-by":"publisher","first-page":"404","DOI":"10.1016\/j.ab.2007.10.027","article-title":"Determination of protein oligomerization state: two approaches based on glutaraldehyde crosslinking","volume":"373","year":"2008","journal-title":"Anal. Biochem."},{"key":"2021112217562941300_BCJ-2018-0791C23","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1146\/annurev.bb.17.060188.001045","article-title":"Secondary structure of proteins through circular dichroism spectroscopy","volume":"17","year":"1988","journal-title":"Annu. Rev. Biophys. Biophys. Chem."},{"key":"2021112217562941300_BCJ-2018-0791C24","first-page":"66","volume-title":"Laser Light Scattering in Biochemistry","author":"Harding","year":"1992"},{"key":"2021112217562941300_BCJ-2018-0791C25","doi-asserted-by":"publisher","first-page":"4027","DOI":"10.1021\/bi100155j","article-title":"Thermodynamics and kinetics of association of antibiotics with the aminoglycoside acetyltransferase (3)-IIIb, a resistance-causing enzyme","volume":"49","year":"2000","journal-title":"Biochemistry"},{"key":"2021112217562941300_BCJ-2018-0791C26","doi-asserted-by":"publisher","first-page":"10243","DOI":"10.1021\/bi060935d","article-title":"Molecular determinants of affinity for aminoglycoside binding to the aminoglycoside nucleotidyl-transferase(200)-Ia","volume":"45","year":"2006","journal-title":"Biochemistry"},{"key":"2021112217562941300_BCJ-2018-0791C27","doi-asserted-by":"publisher","first-page":"7519","DOI":"10.1021\/bi020190l","article-title":"Thermodynamics of aminoglycoside and acyl-coenzyme a binding to the Salmonella enterica AAC(6\u2032)-Iy aminoglycoside N-acetyltransferase","volume":"41","year":"2001","journal-title":"Biochemistry"},{"key":"2021112217562941300_BCJ-2018-0791C28","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1016\/S0968-0004(97)01034-7","article-title":"GCN5-related histone N-acetyltransferases belong to a diverse superfamily that includes the yeast SPT10 protein","volume":"22","year":"1997","journal-title":"Trends Biochem. Sci."},{"key":"2021112217562941300_BCJ-2018-0791C29","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1615\/CritRevEukaryotGeneExpr.2014007988","article-title":"The roles of bacterial GCN5-related N-acetyltransferases","volume":"24","year":"2014","journal-title":"Crit. Rev. Eukaryot. Gene Expr."},{"key":"2021112217562941300_BCJ-2018-0791C30","doi-asserted-by":"publisher","first-page":"402","DOI":"10.15698\/mic2017.12.602","article-title":"Aminoglycoside resistance profile and structural architecture of the aminoglycoside acetyltransferase AAC(6\u2032)-Im","volume":"4","year":"2017","journal-title":"Microb. Cell"},{"key":"2021112217562941300_BCJ-2018-0791C31","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1006\/tpbi.2002.1594","article-title":"Phylogenetic analysis and gene functional predictions: phylogenomics in action","volume":"61","year":"2002","journal-title":"Theor. Popul. Biol."},{"key":"2021112217562941300_BCJ-2018-0791C32","doi-asserted-by":"publisher","first-page":"W545","DOI":"10.1093\/nar\/gkq366","article-title":"Dali server: conservation mapping in 3D","volume":"38","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"2021112217562941300_BCJ-2018-0791C33","doi-asserted-by":"publisher","first-page":"1233","DOI":"10.1099\/jmm.0.45716-0","article-title":"Diversity of aminoglycoside-resistance genes and their association with class1 integrons among strains of pan-European A. baumannii clone","volume":"53","year":"2004","journal-title":"J. Med. Microbiol."},{"key":"2021112217562941300_BCJ-2018-0791C34","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1093\/jac\/dkn454","article-title":"Antibiotic resistance determinants in nosocomial strains of multidrug-resistant Acinetobacter baumannii","volume":"63","year":"2009","journal-title":"J. Antimicrob. Chemother."},{"key":"2021112217562941300_BCJ-2018-0791C35","doi-asserted-by":"publisher","first-page":"5766","DOI":"10.1093\/nar\/gkh910","article-title":"Unique features revealed by the genome sequence of Acinetobacter sp. ADP1, a versatile and naturally transformation competent bacterium","volume":"32","year":"2004","journal-title":"Nucleic Acids Res."},{"key":"2021112217562941300_BCJ-2018-0791C36","doi-asserted-by":"publisher","first-page":"9442","DOI":"10.1073\/pnas.1502966112","article-title":"A multidrug resistance plasmid contains the molecular switch for type VI secretion in Acinetobacter baumannii","volume":"30","year":"2015","journal-title":"Proc. Natl Acad. Sci. U.S.A."},{"key":"2021112217562941300_BCJ-2018-0791C37","doi-asserted-by":"publisher","first-page":"2970","DOI":"10.1111\/j.1462-2920.2009.01972.x","article-title":"The role of antibiotics and antibiotic resistance in nature","volume":"11","year":"2009","journal-title":"Environ. Microbiol."},{"key":"2021112217562941300_BCJ-2018-0791C38","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1016\/S0022-2836(02)00400-X","article-title":"Evolution of an antibiotic resistance enzyme constrained by stability and activity trade-offs","volume":"320","year":"2002","journal-title":"J. Mol. Biol."}],"container-title":["Biochemical Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/biochemj\/article-pdf\/476\/5\/795\/861109\/bcj-2018-0791.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/biochemj\/article-pdf\/476\/5\/795\/861109\/bcj-2018-0791.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,23]],"date-time":"2021-11-23T02:23:58Z","timestamp":1637634238000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/biochemj\/article\/476\/5\/795\/219541\/Aminoglycoside-antibiotic-resistance-conferred-by"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,3,6]]},"references-count":38,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2019,3,15]]}},"URL":"https:\/\/doi.org\/10.1042\/bcj20180791","relation":{},"ISSN":["0264-6021","1470-8728"],"issn-type":[{"type":"print","value":"0264-6021"},{"type":"electronic","value":"1470-8728"}],"subject":[],"published":{"date-parts":[[2019,3,6]]}}}