{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T19:23:33Z","timestamp":1790882613588,"version":"4.1.0"},"reference-count":48,"publisher":"Springer Science and Business Media LLC","issue":"9","license":[{"start":{"date-parts":[[2025,7,16]],"date-time":"2025-07-16T00:00:00Z","timestamp":1752624000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,7,16]],"date-time":"2025-07-16T00:00:00Z","timestamp":1752624000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R15AI047115"],"award-info":[{"award-number":["R15AI047115"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["SC3GM125556"],"award-info":[{"award-number":["SC3GM125556"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006545","name":"National Institute on Minority Health and Health Disparities","doi-asserted-by":"publisher","award":["T37MD001368"],"award-info":[{"award-number":["T37MD001368"]}],"id":[{"id":"10.13039\/100006545","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Curr Microbiol"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>The ongoing antibiotic resistance crisis is one of the most pressing public health challenges. Multidrug-resistant bacterial pathogens are reaching the point where some are becoming untreatable. Consequently, besides discovering novel antibiotics, alternative strategies must be explored to manage the problem. One approach is developing inhibitors that overcome resistance to antibiotics currently in use. Resistance to aminoglycosides such as amikacin is mainly due to aminoglycoside-modifying enzymes. Despite being refractory to most resistance enzymes, the semisynthetic amikacin is inactivated by aminoglycoside 6\u2032-<jats:italic>N<\/jats:italic>-acetyltransferases type I [AAC(6\u2032)-I], of which AAC(6\u2032)-Ib is the most common in Gram-negative pathogens. The discovery that certain divalent and monovalent cations interfere with enzymatic acetylation catalyzed by AAC(6\u2032)-Ib opens possibilities for developing formulations combining antibiotics with these cations to enhance efficacy. Addition of CdCl\u2082 to in vitro enzymatic assays inhibited transfer of an acetyl group to the 6\u2032-<jats:italic>N<\/jats:italic> position of amikacin, kanamycin, and tobramycin. Hence, Cd<jats:sup>2<\/jats:sup>\u207a is a potential adjuvant to aminoglycosides for treating AAC(6\u2032)-Ib-mediated resistant infections. It was initially disappointing that, as with other divalent cations, CdCl\u2082 addition to cultures of bacteria harboring AAC(6\u2032)-Ib did not reverse resistance. However, the inhibitory action of Cd<jats:sup>2<\/jats:sup>\u207a became evident when combined with the ionophore pyrithione. The complex efficiently inhibited resistance in <jats:italic>Acinetobacter baumann<\/jats:italic>ii and <jats:italic>Klebsiella pneumoniae<\/jats:italic> harboring AAC(6\u2032)-Ib. Furthermore, the combination inhibited amikacin resistance in carbapenem-resistant <jats:italic>K. pneumoniae<\/jats:italic> clinical isolates. These results add another cation to the arsenal of potential aminoglycoside adjuvants, which could be developed alone or in coordination complexes with ionophores to treat multidrug-resistant infections.<\/jats:p>","DOI":"10.1007\/s00284-025-04372-1","type":"journal-article","created":{"date-parts":[[2025,7,16]],"date-time":"2025-07-16T13:28:42Z","timestamp":1752672522000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Inhibiting Amikacin Resistance in Multidrug-Resistant Bacteria with Cadmium and Pyrithione"],"prefix":"10.1007","volume":"82","author":[{"given":"Angel J.","family":"Maga\u00f1a","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Ngo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth","family":"Burgos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina","family":"Dominguez Maldonado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omniya","family":"Abdelmaksoud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Sklenicka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tung","family":"Tran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando","family":"Pasteran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ver\u00f3nica","family":"Jimenez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda S.","family":"Ramirez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6298-7811","authenticated-orcid":false,"given":"Marcelo E.","family":"Tolmasky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,16]]},"reference":[{"key":"4372_CR1","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1016\/j.drup.2010.08.003","volume":"13","author":"MS Ramirez","year":"2010","unstructured":"Ramirez MS, Tolmasky ME (2010) Aminoglycoside modifying enzymes. Drug Resist Updat 13:151\u2013171. https:\/\/doi.org\/10.1016\/j.drup.2010.08.003","journal-title":"Drug Resist Updat"},{"key":"4372_CR2","doi-asserted-by":"publisher","first-page":"e0003622","DOI":"10.1128\/mmbr.00036-22","volume":"87","author":"M Lang","year":"2023","unstructured":"Lang M, Carvalho A, Baharoglu Z, Mazel D (2023) Aminoglycoside uptake, stress, and potentiation in Gram-negative bacteria: new therapies with old molecules. Microbiol Mol Biol Rev 87:e0003622. https:\/\/doi.org\/10.1128\/mmbr.00036-22","journal-title":"Microbiol Mol Biol Rev"},{"key":"4372_CR3","doi-asserted-by":"publisher","first-page":"a027029","DOI":"10.1101\/cshperspect.a027029","volume":"6","author":"KM Krause","year":"2016","unstructured":"Krause KM, Serio AW, Kane TR, Connolly LE (2016) Aminoglycosides: an overview. Cold Spring Harb Perspect Med 6:a027029. https:\/\/doi.org\/10.1101\/cshperspect.a027029","journal-title":"Cold Spring Harb Perspect Med"},{"key":"4372_CR4","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1021\/acsinfecdis.9b00441","volume":"6","author":"EC Bottger","year":"2020","unstructured":"Bottger EC, Crich D (2020) Aminoglycosides: time for the resurrection of a neglected class of antibacterials? ACS Infect Dis 6:168\u2013172. https:\/\/doi.org\/10.1021\/acsinfecdis.9b00441","journal-title":"ACS Infect Dis"},{"key":"4372_CR5","doi-asserted-by":"publisher","first-page":"2267","DOI":"10.3390\/molecules22122267","volume":"22","author":"MS Ramirez","year":"2017","unstructured":"Ramirez MS, Tolmasky ME (2017) Amikacin: uses, resistance, and prospects for inhibition. Molecules 22:2267. https:\/\/doi.org\/10.3390\/molecules22122267","journal-title":"Molecules"},{"key":"4372_CR6","first-page":"35","volume-title":"Enzyme-mediated resistance to antibiotics: mechanisms, dissemination, and prospects for inhibition","author":"ME Tolmasky","year":"2007","unstructured":"Tolmasky ME (2007) Aminoglycoside-modifying enzymes: characteristics, localization, and dissemination. In: Bonomo RA, Tolmasky ME (eds) Enzyme-mediated resistance to antibiotics: mechanisms, dissemination, and prospects for inhibition. ASM Press, Washington, DC, pp 35\u201352"},{"key":"4372_CR7","doi-asserted-by":"publisher","first-page":"121","DOI":"10.3389\/fmicb.2013.00121","volume":"4","author":"MS Ramirez","year":"2013","unstructured":"Ramirez MS, Nikolaidis N, Tolmasky ME (2013) Rise and dissemination of aminoglycoside resistance: the aac(6\u2032)-Ib paradigm. Front Microbiol 4:121. https:\/\/doi.org\/10.3389\/fmicb.2013.00121","journal-title":"Front Microbiol"},{"key":"4372_CR8","doi-asserted-by":"publisher","first-page":"1285","DOI":"10.4155\/fmc.13.80","volume":"5","author":"KJ Labby","year":"2013","unstructured":"Labby KJ, Garneau-Tsodikova S (2013) Strategies to overcome the action of aminoglycoside-modifying enzymes for treating resistant bacterial infections. Future Med Chem 5:1285\u20131309. https:\/\/doi.org\/10.4155\/fmc.13.80","journal-title":"Future Med Chem"},{"key":"4372_CR9","first-page":"1","volume-title":"Frontiers in clinical drug research-anti infectives","author":"ME Tolmasky","year":"2017","unstructured":"Tolmasky ME (2017) Strategies to prolong the useful life of existing antibiotics and help overcoming the antibiotic resistance crisis. In: ur-Rhaman A (ed) Frontiers in clinical drug research-anti infectives, vol 1. Bentham Books, Sharjah, pp 1\u201327"},{"key":"4372_CR10","doi-asserted-by":"publisher","first-page":"e00789","DOI":"10.1101\/2023.09.05.556435","volume":"3","author":"OD d\u2019Acoz","year":"2024","unstructured":"d\u2019Acoz OD, Hue F, Ye T, Wang L, Leroux M, Rajngewerc L, Tran T, Phan K, Ramirez MS, Reisner W, Tolmasky ME, Reyes-Lamothe R (2024) Dynamics and quantitative contribution of the aminoglycoside 6\u2032-N-acetyltransferase type Ib [AAC(6\u2032)-Ib] to amikacin resistance. mSphere 3:e00789-00723. https:\/\/doi.org\/10.1101\/2023.09.05.556435","journal-title":"mSphere"},{"key":"4372_CR11","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1039\/C5MD00316D","volume":"7","author":"K Chiem","year":"2016","unstructured":"Chiem K, Jani S, Fuentes B, Lin DL, Rasche ME, Tolmasky ME (2016) Identification of an inhibitor of the aminoglycoside 6\u2032-N-acetyltransferase type Ib [AAC(6\u2032)-Ib] by Glide molecular docking. Medchemcomm 7:184\u2013189. https:\/\/doi.org\/10.1039\/C5MD00316D","journal-title":"Medchemcomm"},{"key":"4372_CR12","doi-asserted-by":"publisher","first-page":"5694","DOI":"10.1016\/j.bmcl.2013.08.016","volume":"23","author":"DL Lin","year":"2013","unstructured":"Lin DL, Tran T, Adams C, Alam JY, Herron SR, Tolmasky ME (2013) Inhibitors of the aminoglycoside 6\u2032-N-acetyltransferase type Ib [AAC(6\u2032)-Ib] identified by in silico molecular docking. Bioorg Med Chem Lett 23:5694\u20135698. https:\/\/doi.org\/10.1016\/j.bmcl.2013.08.016","journal-title":"Bioorg Med Chem Lett"},{"key":"4372_CR13","doi-asserted-by":"publisher","first-page":"136976","DOI":"10.1016\/j.ijbiomac.2024.136976","volume":"281","author":"D Prabhu","year":"2024","unstructured":"Prabhu D, Shankari G, Rajamanikandan S, Jeyakanthan J, Velusamy P, Gopinath SCB, Pattabi S (2024) Designing potential lead compounds targeting aminoglycoside N (6\u2032)-acetyltransferase in Serratia marcescens: A drug discovery strategy. Int J Biol Macromol 281:136976. https:\/\/doi.org\/10.1016\/j.ijbiomac.2024.136976","journal-title":"Int J Biol Macromol"},{"key":"4372_CR14","doi-asserted-by":"publisher","first-page":"19381","DOI":"10.1038\/s41598-020-76355-0","volume":"10","author":"S Ahmed","year":"2020","unstructured":"Ahmed S, Sony SA, Chowdhury MB, Ullah MM, Paul S, Hossain T (2020) Retention of antibiotic activity against resistant bacteria harbouring aminoglycoside-N-acetyltransferase enzyme by adjuvants: a combination of in-silico and in-vitro study. Sci Rep 10:19381. https:\/\/doi.org\/10.1038\/s41598-020-76355-0","journal-title":"Sci Rep"},{"key":"4372_CR15","doi-asserted-by":"publisher","first-page":"752","DOI":"10.1016\/j.ijantimicag.2018.01.019","volume":"51","author":"T Tran","year":"2018","unstructured":"Tran T, Chiem K, Jani S, Arivett BA, Lin DL, Lad R, Jimenez V, Farone MB, Debevec G, Santos R, Giulianotti M, Pinilla C, Tolmasky ME (2018) Identification of a small molecule inhibitor of the aminoglycoside 6\u2032-N-acetyltransferase type Ib [AAC(6\u2032)-Ib] using mixture-based combinatorial libraries. Int J Antimicrob Agents 51:752\u2013761. https:\/\/doi.org\/10.1016\/j.ijantimicag.2018.01.019","journal-title":"Int J Antimicrob Agents"},{"key":"4372_CR16","doi-asserted-by":"publisher","first-page":"1218","DOI":"10.3390\/biomedicines9091218","volume":"9","author":"K Rocha","year":"2021","unstructured":"Rocha K, Magallon J, Reeves C, Phan K, Vu P, Oakley-Havens CL, Kwan S, Ramirez MS, LaVoi T, Donow H, Chapagain P, Santos R, Pinilla C, Giulianotti MA, Tolmasky ME (2021) Inhibition of aminoglycoside 6\u2032-N-acetyltransferase type Ib (AAC(6\u2032)-Ib): structure-activity relationship of substituted pyrrolidine pentamine derivatives as inhibitors. Biomedicines 9:1218. https:\/\/doi.org\/10.3390\/biomedicines9091218","journal-title":"Biomedicines"},{"key":"4372_CR17","doi-asserted-by":"publisher","DOI":"10.3390\/antibiotics13070672","author":"J Sklenicka","year":"2024","unstructured":"Sklenicka J, Tran T, Ramirez MS, Donow HM, Magana AJ, LaVoi T, Mamun Y, Jimenez V, Chapagain P, Santos R, Pinilla C, Giulianotti MA, Tolmasky ME (2024) Structure-activity relationship of pyrrolidine pentamine derivatives as inhibitors of the aminoglycoside 6\u2032-N-acetyltransferase type Ib. Antibiotics (Basel). https:\/\/doi.org\/10.3390\/antibiotics13070672","journal-title":"Antibiotics (Basel)"},{"key":"4372_CR18","doi-asserted-by":"publisher","first-page":"5798","DOI":"10.1128\/AAC.01304-15","volume":"59","author":"C Lopez","year":"2015","unstructured":"Lopez C, Arivett BA, Actis LA, Tolmasky ME (2015) Inhibition of AAC(6\u2032)-Ib-mediated resistance to amikacin in Acinetobacter baumannii by an antisense peptide-conjugated 2\u2032,4\u2032-bridged nucleic acid-NC-DNA hybrid oligomer. Antimicrob Agents Chemother 59:5798\u20135803. https:\/\/doi.org\/10.1128\/AAC.01304-15","journal-title":"Antimicrob Agents Chemother"},{"key":"4372_CR19","doi-asserted-by":"publisher","first-page":"13230","DOI":"10.1073\/pnas.0906529106","volume":"106","author":"AJ Soler Bistue","year":"2009","unstructured":"Soler Bistue AJ, Martin FA, Vozza N, Ha H, Joaquin JC, Zorreguieta A, Tolmasky ME (2009) Inhibition of aac(6\u2032)-Ib-mediated amikacin resistance by nuclease-resistant external guide sequences in bacteria. Proc Natl Acad Sci USA 106:13230\u201313235. https:\/\/doi.org\/10.1073\/pnas.0906529106","journal-title":"Proc Natl Acad Sci USA"},{"key":"4372_CR20","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/j.ijantimicag.2017.08.002","volume":"51","author":"K Chiem","year":"2018","unstructured":"Chiem K, Hue F, Magallon J, Tolmasky ME (2018) Inhibition of aminoglycoside 6\u2032-N-acetyltransferase type Ib-mediated amikacin resistance by zinc complexed with clioquinol, an ionophore active against tumors and neurodegenerative diseases. Int J Antimicrob Agents 51:271\u2013273. https:\/\/doi.org\/10.1016\/j.ijantimicag.2017.08.002","journal-title":"Int J Antimicrob Agents"},{"key":"4372_CR21","doi-asserted-by":"publisher","first-page":"4148","DOI":"10.1128\/AAC.00885-15","volume":"59","author":"Y Li","year":"2015","unstructured":"Li Y, Green KD, Johnson BR, Garneau-Tsodikova S (2015) Inhibition of aminoglycoside acetyltransferase resistance enzymes by metal salts. Antimicrob Agents Chemother 59:4148\u20134156. https:\/\/doi.org\/10.1128\/AAC.00885-15","journal-title":"Antimicrob Agents Chemother"},{"key":"4372_CR22","doi-asserted-by":"publisher","first-page":"4238","DOI":"10.1128\/AAC.00129-14","volume":"58","author":"DL Lin","year":"2014","unstructured":"Lin DL, Tran T, Alam JY, Herron SR, Ramirez MS, Tolmasky ME (2014) Inhibition of aminoglycoside 6\u2032-N-acetyltransferase type Ib by zinc: reversal of amikacin resistance in Acinetobacter baumannii and Escherichia coli by a zinc ionophore. Antimicrob Agents Chemother 58:4238\u20134241. https:\/\/doi.org\/10.1128\/AAC.00129-14","journal-title":"Antimicrob Agents Chemother"},{"key":"4372_CR23","doi-asserted-by":"publisher","first-page":"29","DOI":"10.3390\/antibiotics10010029","volume":"10","author":"CM Reeves","year":"2020","unstructured":"Reeves CM, Magallon J, Rocha K, Tran T, Phan K, Vu P, Yi Y, Oakley-Havens CL, Cedano J, Jimenez V, Ramirez MS, Tolmasky ME (2020) Aminoglycoside 6\u2032-N-acetyltransferase type Ib [AAC(6\u2032)-Ib]-mediated aminoglycoside resistance: phenotypic conversion to susceptibility by silver ions. Antibiotics (Basel) 10:29. https:\/\/doi.org\/10.3390\/antibiotics10010029","journal-title":"Antibiotics (Basel)"},{"key":"4372_CR24","doi-asserted-by":"publisher","first-page":"5851","DOI":"10.1128\/AAC.01106-15","volume":"59","author":"K Chiem","year":"2015","unstructured":"Chiem K, Fuentes BA, Lin DL, Tran T, Jackson A, Ramirez MS, Tolmasky ME (2015) Inhibition of aminoglycoside 6\u2032-N-acetyltransferase type Ib-mediated amikacin resistance in Klebsiella pneumoniae by zinc and copper pyrithione. Antimicrob Agents Chemother 59:5851\u20135853. https:\/\/doi.org\/10.1128\/AAC.01106-15","journal-title":"Antimicrob Agents Chemother"},{"key":"4372_CR25","doi-asserted-by":"publisher","first-page":"e0217602","DOI":"10.1371\/journal.pone.0217602","volume":"14","author":"J Magallon","year":"2019","unstructured":"Magallon J, Chiem K, Tran T, Ramirez MS, Jimenez V, Tolmasky ME (2019) Restoration of susceptibility to amikacin by 8-hydroxyquinoline analogs complexed to zinc. PLoS ONE 14:e0217602. https:\/\/doi.org\/10.1371\/journal.pone.0217602","journal-title":"PLoS ONE"},{"key":"4372_CR26","doi-asserted-by":"publisher","first-page":"106442","DOI":"10.1016\/j.ijantimicag.2021.106442","volume":"58","author":"J Magallon","year":"2021","unstructured":"Magallon J, Vu P, Reeves C, Kwan S, Phan K, Oakley-Havens C, Ramirez MS, Tolmasky ME (2021) Amikacin in combination with zinc pyrithione prevents growth of a carbapenem-resistant\/multidrug-resistant Klebsiella pneumoniae isolate. Int J Antimicrob Agents 58:106442. https:\/\/doi.org\/10.1016\/j.ijantimicag.2021.106442","journal-title":"Int J Antimicrob Agents"},{"key":"4372_CR27","doi-asserted-by":"publisher","first-page":"236","DOI":"10.3390\/ph16020236","volume":"16","author":"D Ngo","year":"2023","unstructured":"Ngo D, Magana AJ, Tran T, Sklenicka J, Phan K, Eykholt B, Jimenez V, Ramirez MS, Tolmasky ME (2023) Inhibition of enzymatic acetylation-mediated resistance to plazomicin by silver ions. Pharmaceuticals (Basel) 16:236. https:\/\/doi.org\/10.3390\/ph16020236","journal-title":"Pharmaceuticals (Basel)"},{"key":"4372_CR28","doi-asserted-by":"publisher","first-page":"e00212","DOI":"10.1128\/genomeA.00212-15","volume":"3","author":"BA Arivett","year":"2015","unstructured":"Arivett BA, Fiester SE, Ream DC, Centron D, Ramirez MS, Tolmasky ME, Actis LA (2015) Draft genome of the multidrug-resistant Acinetobacter baumannii strain A155 clinical isolate. Genome Announc 3:e00212-00215. https:\/\/doi.org\/10.1128\/genomeA.00212-15","journal-title":"Genome Announc"},{"key":"4372_CR29","doi-asserted-by":"publisher","first-page":"E254","DOI":"10.1111\/j.1469-0691.2012.03886.x","volume":"18","author":"MS Ramirez","year":"2012","unstructured":"Ramirez MS, Xie G, Marshall SH, Hujer KM, Chain PS, Bonomo RA, Tolmasky ME (2012) Multidrug-resistant (MDR) Klebsiella pneumoniae clinical isolates: a zone of high heterogeneity (HHZ) as a tool for epidemiological studies. Clin Microbiol Infect 18:E254-258. https:\/\/doi.org\/10.1111\/j.1469-0691.2012.03886.x","journal-title":"Clin Microbiol Infect"},{"key":"4372_CR30","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.jgar.2024.11.007","volume":"40","author":"AJ Magana","year":"2025","unstructured":"Magana AJ, Ngo D, Faccone D, Gomez S, Corso A, Pasteran F, Ramirez MS, Tolmasky ME (2025) Amikacin, in combination with cations, prevents growth of a carbapenem-resistant\/multidrug-resistant Klebsiella pneumoniae strain isolated from a patient with COVID-19. J Glob Antimicrob Resist 40:8\u201310. https:\/\/doi.org\/10.1016\/j.jgar.2024.11.007","journal-title":"J Glob Antimicrob Resist"},{"key":"4372_CR31","unstructured":"Gomez S, Martino F, Sanz M, Escalante J, Mendieta J, Lucero C, Ceriana P, Pasteran F, Corso A, Ramirez MS, Faccone D (2025) Emerging resistance to novel beta-lactam beta-lactamase inhibitor combinations in Klebsiella pneumoniae bearing KPC variants. J Antimicrob Chemother submitted for publication"},{"key":"4372_CR32","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1016\/0076-6879(75)43124-x","volume":"43","author":"MJ Haas","year":"1975","unstructured":"Haas MJ, Dowding JE (1975) Aminoglycoside-modifying enzymes. Methods Enzymol 43:611\u2013628. https:\/\/doi.org\/10.1016\/0076-6879(75)43124-x","journal-title":"Methods Enzymol"},{"key":"4372_CR33","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1128\/AAC.30.2.315","volume":"30","author":"ME Tolmasky","year":"1986","unstructured":"Tolmasky ME, Roberts M, Woloj M, Crosa JH (1986) Molecular cloning of amikacin resistance determinants from a Klebsiella pneumoniae plasmid. Antimicrob Agents Chemother 30:315\u2013320. https:\/\/doi.org\/10.1128\/AAC.30.2.315","journal-title":"Antimicrob Agents Chemother"},{"key":"4372_CR34","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1128\/AAC.29.2.315","volume":"29","author":"M Woloj","year":"1986","unstructured":"Woloj M, Tolmasky ME, Roberts MC, Crosa JH (1986) Plasmid-encoded amikacin resistance in multiresistant strains of Klebsiella pneumoniae isolated from neonates with meningitis. Antimicrob Agents Chemother 29:315\u2013319. https:\/\/doi.org\/10.1128\/AAC.29.2.315","journal-title":"Antimicrob Agents Chemother"},{"key":"4372_CR35","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1099\/0022-1317-36-1-59","volume":"36","author":"FL Graham","year":"1977","unstructured":"Graham FL, Smiley J, Russell WC, Nairn R (1977) Characteristics of a human cell line transformed by DNA from human adenovirus type 5. J Gen Virol 36:59\u201374. https:\/\/doi.org\/10.1099\/0022-1317-36-1-59","journal-title":"J Gen Virol"},{"key":"4372_CR36","doi-asserted-by":"publisher","first-page":"1042","DOI":"10.1093\/nar\/gkt918","volume":"42","author":"R Reyes-Lamothe","year":"2014","unstructured":"Reyes-Lamothe R, Tran T, Meas D, Lee L, Li AM, Sherratt DJ, Tolmasky ME (2014) High-copy bacterial plasmids diffuse in the nucleoid-free space, replicate stochastically and are randomly partitioned at cell division. Nucleic Acids Res 42:1042\u20131051. https:\/\/doi.org\/10.1093\/nar\/gkt918","journal-title":"Nucleic Acids Res"},{"key":"4372_CR37","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1111\/j.1365-2672.1988.tb03384.x","volume":"64","author":"MM Khattar","year":"1988","unstructured":"Khattar MM, Salt WG, Stretton RJ (1988) The influence of pyrithione on the growth of micro-organisms. J Appl Bacteriol 64:265\u2013272. https:\/\/doi.org\/10.1111\/j.1365-2672.1988.tb03384.x","journal-title":"J Appl Bacteriol"},{"key":"4372_CR38","doi-asserted-by":"publisher","first-page":"4943","DOI":"10.1128\/AAC.00296-11","volume":"55","author":"KM Papp-Wallace","year":"2011","unstructured":"Papp-Wallace KM, Endimiani A, Taracila MA, Bonomo RA (2011) Carbapenems: past, present, and future. Antimicrob Agents Chemother 55:4943\u20134960. https:\/\/doi.org\/10.1128\/AAC.00296-11","journal-title":"Antimicrob Agents Chemother"},{"key":"4372_CR39","doi-asserted-by":"publisher","first-page":"1290","DOI":"10.1093\/cid\/cix893","volume":"66","author":"RA Bonomo","year":"2018","unstructured":"Bonomo RA, Burd EM, Conly J, Limbago BM, Poirel L, Segre JA, Westblade LF (2018) Carbapenemase-producing organisms: a global scourge. Clin Infect Dis 66:1290\u20131297. https:\/\/doi.org\/10.1093\/cid\/cix893","journal-title":"Clin Infect Dis"},{"key":"4372_CR40","volume-title":"WHO bacterial priority pathogens list, 2024: bacterial pathogens of public health importance to guide research, development and strategies to prevent and control antimicrobial resistance","author":"World-Health-Organization","year":"2024","unstructured":"World-Health-Organization (2024) WHO bacterial priority pathogens list, 2024: bacterial pathogens of public health importance to guide research, development and strategies to prevent and control antimicrobial resistance. World Health Organization, Geneva"},{"key":"4372_CR41","doi-asserted-by":"publisher","first-page":"2548","DOI":"10.3390\/microorganisms12122548","volume":"12","author":"TA Chen","year":"2024","unstructured":"Chen TA, Chuang YT, Lin CH (2024) A decade-long review of the virulence, resistance, and epidemiological risks of Klebsiella pneumoniae in ICUs. Microorganisms 12:2548. https:\/\/doi.org\/10.3390\/microorganisms12122548","journal-title":"Microorganisms"},{"key":"4372_CR42","first-page":"65","volume":"131","author":"HW Boucher","year":"2020","unstructured":"Boucher HW (2020) Bad bugs, no drugs 2002\u20132020: progress, challenges, and call to action. Trans Am Clin Climatol Assoc 131:65\u201371","journal-title":"Trans Am Clin Climatol Assoc"},{"key":"4372_CR43","doi-asserted-by":"publisher","first-page":"e14510","DOI":"10.1111\/1751-7915.14510","volume":"17","author":"H Brussow","year":"2024","unstructured":"Brussow H (2024) The antibiotic resistance crisis and the development of new antibiotics. Microb Biotechnol 17:e14510. https:\/\/doi.org\/10.1111\/1751-7915.14510","journal-title":"Microb Biotechnol"},{"key":"4372_CR44","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1080\/1040841X.2017.1313811","volume":"44","author":"PL Lam","year":"2018","unstructured":"Lam PL, Lee KKH, Wong RSM, Cheng GYM, Bian ZX, Chui CH, Gambari R (2018) Recent advances on topical antimicrobials for skin and soft tissue infections and their safety concerns. Crit Rev Microbiol 44:40\u201378. https:\/\/doi.org\/10.1080\/1040841X.2017.1313811","journal-title":"Crit Rev Microbiol"},{"key":"4372_CR45","doi-asserted-by":"publisher","first-page":"84","DOI":"10.4103\/tjo.TJO-D-22-00101","volume":"13","author":"R Dhiman","year":"2023","unstructured":"Dhiman R, Sharma N, Chauhan J (2023) Klebsiella keratitis presenting as a ring infiltrate in an adolescent girl. Taiwan J Ophthalmol 13:84\u201387. https:\/\/doi.org\/10.4103\/tjo.TJO-D-22-00101","journal-title":"Taiwan J Ophthalmol"},{"key":"4372_CR46","doi-asserted-by":"publisher","first-page":"ovae134","DOI":"10.1093\/lambio\/ovae134","volume":"78","author":"PM Francis","year":"2025","unstructured":"Francis PM, Vinod V, Kumar VA, Mohan CG, Biswas R (2025) Development and evaluation of amikacin-loaded carbopol hydrogel for topical treatment of Mycobacterium marinum skin infections. Lett Appl Microbiol 78:ovae134. https:\/\/doi.org\/10.1093\/lambio\/ovae134","journal-title":"Lett Appl Microbiol"},{"key":"4372_CR47","doi-asserted-by":"publisher","first-page":"2323","DOI":"10.1016\/j.ccr.2005.04.027","volume":"249","author":"H Koz\u0142owski","year":"2005","unstructured":"Koz\u0142owski H, Kowalik-Jankowska T, Je\u017cowska-Bojczuk M (2005) Chemical and biological aspects of Cu2+ interactions with peptides and aminoglycosides. Coord Chem Rev 249:2323\u20132334. https:\/\/doi.org\/10.1016\/j.ccr.2005.04.027","journal-title":"Coord Chem Rev"},{"key":"4372_CR48","doi-asserted-by":"publisher","first-page":"e28","DOI":"10.1016\/S1473-3099(20)30868-9","volume":"22","author":"MF Mojica","year":"2022","unstructured":"Mojica MF, Rossi MA, Vila AJ, Bonomo RA (2022) The urgent need for metallo-beta-lactamase inhibitors: an unattended global threat. Lancet Infect Dis 22:e28\u2013e34. https:\/\/doi.org\/10.1016\/S1473-3099(20)30868-9","journal-title":"Lancet Infect Dis"}],"container-title":["Current Microbiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00284-025-04372-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00284-025-04372-1\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00284-025-04372-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T04:44:20Z","timestamp":1756442660000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00284-025-04372-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,16]]},"references-count":48,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2025,9]]}},"alternative-id":["4372"],"URL":"https:\/\/doi.org\/10.1007\/s00284-025-04372-1","relation":{},"ISSN":["0343-8651","1432-0991"],"issn-type":[{"value":"0343-8651","type":"print"},{"value":"1432-0991","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,16]]},"assertion":[{"value":"7 April 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 July 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 July 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors have no relevant financial or non-financial interests to disclose.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interests"}},{"value":"All authors have read and provided consent for the manuscript to be published.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for Publication"}}],"article-number":"389"}}