{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T14:08:36Z","timestamp":1789135716927,"version":"build-2803163510"},"reference-count":62,"publisher":"American Chemical Society (ACS)","issue":"9","license":[{"start":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T00:00:00Z","timestamp":1785974400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004271","name":"Sapienza Universit? di Roma","doi-asserted-by":"publisher","award":["RG124190CBD34B9D"],"award-info":[{"award-number":["RG124190CBD34B9D"]}],"id":[{"id":"10.13039\/501100004271","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008385","name":"Fondazione per la Ricerca sulla Fibrosi Cistica","doi-asserted-by":"publisher","award":["FFC6\/2025"],"award-info":[{"award-number":["FFC6\/2025"]}],"id":[{"id":"10.13039\/501100008385","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100031478","name":"NextGenerationEU","doi-asserted-by":"publisher","award":["PE00000007"],"award-info":[{"award-number":["PE00000007"]}],"id":[{"id":"10.13039\/100031478","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004588","name":"Istituto Pasteur-Fondazione Cenci Bolognetti","doi-asserted-by":"publisher","award":["Anna Tramontano Call 2024"],"award-info":[{"award-number":["Anna Tramontano Call 2024"]}],"id":[{"id":"10.13039\/501100004588","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Carbapenemase-producing Klebsiella pneumoniae represents a major clinical threat due to the multidrug-resistant phenotype of this Gram-negative bacterium and to the limited available therapeutic options. Currently, antimicrobial peptides are regarded as promising candidates for the development of novel anti-infective strategies. In this study, the antimicrobial activity of the frog skin-derived antimicrobial peptide Esc(1-21) and its three analogs, an Aib-containing peptide and two variants bearing d-amino acids (i.e., the diastereomer Esc(1-21)-1c and [Aib8]-Esc(1-21)-1c isoform), was evaluated against a panel of clinical carbapenemase-producing Klebsiella pneumoniae isolates. In addition, the ability of these d-amino acid-containing peptides to potentiate the effectiveness of ceftazidime, a widely used third-generation cephalosporin for treatment of severe Gram-negative bacterial infections, was investigated. Mechanistic analyses revealed that Esc(1-21)-1c promotes outer membrane permeabilization, thereby facilitating ceftazidime entry into the periplasmic space. Notably, the peptide\/ceftazidime combination treatment resulted in enhanced outer membrane destabilization and increased cytoplasmic membrane perturbation compared to the peptide alone. These findings support a self-reinforcing mechanism in which ceftazidime-mediated cell wall damage further destabilizes the bacterial envelope, promoting additional peptide uptake and amplifying cytoplasmic membrane disruption. Time\u2013kill assays confirmed the superior bactericidal activity of the peptide\/ceftazidime combination compared to either agent used alone. Importantly, no outer membrane perturbation was observed in a strain lacking a synergistic response, suggesting that membrane susceptibility is a key determinant of this cooperative interaction. Overall, these results highlight the potential of Esc-derived peptides as adjuvants capable of restoring \u03b2-lactam efficacy against multidrug-resistant carbapenemase-producing Klebsiella pneumoniae, offering a promising strategy to combat antimicrobial resistance.<\/jats:p>","DOI":"10.1021\/acsinfecdis.6c00366","type":"journal-article","created":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T01:01:29Z","timestamp":1786064489000},"page":"3169-3178","source":"Crossref","is-referenced-by-count":0,"title":["Esculentin-1a\nDerived Peptides Potentiate Ceftazidime\nActivity against Multidrug-Resistant KPC-Producing\n                    <i>Klebsiella pneumoniae<\/i>"],"prefix":"10.1021","volume":"12","author":[{"given":"Dania","family":"Al Ismail","sequence":"first","affiliation":[{"name":"Sapienza University of Rome , , ,","place":["Rome, Italy, 00161"]},{"name":"Sapienza University of Rome , , ,","place":["Rome, Italy, 00185"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Vetrano","sequence":"additional","affiliation":[{"name":"Sapienza University of Rome , , ,","place":["Rome, Italy, 00161"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3683-9704","authenticated-orcid":true,"given":"Luisa","family":"Torrini","sequence":"additional","affiliation":[{"name":"Sapienza University of Rome , , ,","place":["Rome, Italy, 00185"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Rosa","family":"Loffredo","sequence":"additional","affiliation":[{"name":"Sapienza University of Rome , , ,","place":["Rome, Italy, 00161"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eeva","family":"Tortellini","sequence":"additional","affiliation":[{"name":"Sapienza University of Rome , , ,","place":["Rome, Italy, 00161"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0832-7975","authenticated-orcid":true,"given":"Alessandra","family":"Oliva","sequence":"additional","affiliation":[{"name":"Sapienza University of Rome , , ,","place":["Rome, Italy, 00185"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1295-1084","authenticated-orcid":true,"given":"Bruno","family":"Casciaro","sequence":"additional","affiliation":[{"name":"Sapienza University of Rome , , ,","place":["Rome, Italy, 00161"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Rossi","sequence":"additional","affiliation":[{"name":"Sapienza University of Rome , , ,","place":["Rome, Italy, 00185"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Carattoli","sequence":"additional","affiliation":[{"name":"Sapienza University of Rome , , ,","place":["Rome, Italy, 00185"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5991-5868","authenticated-orcid":true,"given":"Maria Luisa","family":"Mangoni","sequence":"additional","affiliation":[{"name":"Sapienza University of Rome , , ,","place":["Rome, Italy, 00161"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,6]]},"reference":[{"key":"2026091109083881100_cit1","doi-asserted-by":"publisher","first-page":"100947","DOI":"10.1016\/j.lanmic.2024.07.010","article-title":"Antimicrobial\nresistance: a concise update","volume":"6","author":"Ho","year":"2025","journal-title":"Lancet Microbe"},{"key":"2026091109083881100_cit2","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1016\/S1473-3099(17)30753-3","article-title":"Discovery, research, and development\nof new antibiotics: the WHO priority list of antibiotic-resistant\nbacteria and tuberculosis","volume":"18","author":"Tacconelli","year":"2018","journal-title":"Lancet Infect Dis"},{"key":"2026091109083881100_cit3","doi-asserted-by":"publisher","first-page":"8888","DOI":"10.1038\/s41598-018-27231-5","article-title":"Exploring\nthe role of unnatural amino acids in antimicrobial peptides","volume":"8","author":"Oliva","year":"2018","journal-title":"Sci. Rep"},{"key":"2026091109083881100_cit4","article-title":"Tackling\ndrug-resistant infections globally: final report and recommendations","volume-title":"The review on antimicrobial resistance","author":"O\u2019Neil","year":"2026"},{"key":"2026091109083881100_cit5","doi-asserted-by":"publisher","first-page":"1348093","DOI":"10.3389\/fcimb.2024.1348093","article-title":"Antibiotic\nresistance of ESKAPE group-microorganisms in health institutions from\nHermosillo and Ciudad Obregon, Sonora, Mexico","volume":"14","author":"Alvarez-Ainza","year":"2024","journal-title":"Front Cell Infect Microbiol"},{"key":"2026091109083881100_cit6","doi-asserted-by":"publisher","first-page":"594","DOI":"10.1093\/jac\/dky499","article-title":"Klebsiella pneumoniae\ncausing urinary tract infections in companion animals and humans:\npopulation structure, antimicrobial resistance and virulence genes","volume":"74","author":"Marques","year":"2019","journal-title":"J. Antimicrob. Chemother."},{"key":"2026091109083881100_cit7","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1128\/MMBR.00078-15","article-title":"Klebsiella pneumoniae:\nGoing on the Offense with a\nStrong Defense","volume":"80","author":"Paczosa","year":"2016","journal-title":"Microbiol Mol. Biol. Rev."},{"key":"2026091109083881100_cit8","doi-asserted-by":"publisher","first-page":"4","DOI":"10.3389\/fcimb.2018.00004","article-title":"Colonization, Infection,\nand the Accessory Genome of\nKlebsiella pneumoniae","volume":"8","author":"Martin","year":"2018","journal-title":"Front Cell Infect Microbiol"},{"key":"2026091109083881100_cit9","doi-asserted-by":"publisher","first-page":"1611","DOI":"10.2147\/IDR.S502175","article-title":"A Comprehensive\nOverview of Klebsiella Pneumoniae: Resistance Dynamics, Clinical Manifestations,\nand Therapeutic Options","volume":"18","author":"Jin","year":"2025","journal-title":"Infect Drug Resist"},{"key":"2026091109083881100_cit10","doi-asserted-by":"publisher","first-page":"100246","DOI":"10.1016\/j.microb.2025.100246","article-title":"Carbapenem-Resistant Klebsiella pneumoniae:\nA comprehensive\nreview of phenotypic and genotypic methods for detection","volume":"6","author":"Mohammadpour","year":"2025","journal-title":"Microbe"},{"key":"2026091109083881100_cit11","doi-asserted-by":"publisher","first-page":"127249","DOI":"10.1016\/j.micres.2022.127249","article-title":"Global spread\nof carbapenem-resistant Enterobacteriaceae: Epidemiological\nfeatures, resistance mechanisms, detection and therapy","volume":"266","author":"Ma","year":"2023","journal-title":"Microbiol Res."},{"key":"2026091109083881100_cit12","doi-asserted-by":"publisher","first-page":"895","DOI":"10.3389\/fmicb.2016.00895","article-title":"Global\nDissemination of Carbapenemase-Producing Klebsiella\npneumoniae: Epidemiology, Genetic Context, Treatment Options, and\nDetection Methods","volume":"7","author":"Lee","year":"2016","journal-title":"Front Microbiol"},{"key":"2026091109083881100_cit13","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.cmi.2023.11.008","article-title":"Attributable\nmortality of infections\ncaused by carbapenem-resistant Enterobacterales: results from a prospective,\nmultinational case-control-control matched cohorts study (EURECA)","volume":"30","author":"Paniagua-Garcia","year":"2024","journal-title":"Clin. Microbiol. Infect."},{"key":"2026091109083881100_cit14","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1080\/07853890.2022.2152484","article-title":"Treatment and diagnosis of severe\nKPC-producing Klebsiella pneumoniae infections: a perspective on what\nhas changed over last decades","volume":"55","author":"Giacobbe","year":"2023","journal-title":"Ann. Med."},{"key":"2026091109083881100_cit15","doi-asserted-by":"publisher","first-page":"677720","DOI":"10.3389\/fmed.2021.677720","article-title":"Current Update\non Intrinsic and Acquired Colistin Resistance Mechanisms in Bacteria","volume":"8","author":"Gogry","year":"2021","journal-title":"Front Med. 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Microbiol."},{"key":"2026091109083881100_cit25","doi-asserted-by":"publisher","first-page":"43763","DOI":"10.1038\/s41598-025-27433-8","article-title":"Ceftazidime\nprescription and antibiotic resistance patterns in a tertiary care\nhospital","volume":"15","author":"Aiesh","year":"2025","journal-title":"Sci. Rep."},{"issue":"1","key":"2026091109083881100_cit26","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/ph19010001","article-title":"Evaluation\nof the In Vitro Synergistic Activity of\nCeftazidime\/Avibactam Against Stenotrophomonas maltophilia Strains\nin Planktonic and Biofilm Cell Cultures","volume":"19","author":"Damar-Celik","year":"2025","journal-title":"Pharmaceuticals\n(Basel)"},{"key":"2026091109083881100_cit27","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1111\/cbdd.12478","article-title":"Antibiotic\nadjuvants: diverse strategies\nfor controlling drug-resistant pathogens","volume":"85","author":"Gill","year":"2015","journal-title":"Chem.\nBiol. 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Sci."},{"key":"2026091109083881100_cit29","doi-asserted-by":"publisher","first-page":"2403","DOI":"10.1021\/acsinfecdis.4c00130","article-title":"Strategic Single-Residue\nSubstitution in the Antimicrobial\nPeptide Esc(1-21) Confers Activity against Staphylococcus aureus,\nIncluding Drug-Resistant and Biofilm Phenotype","volume":"10","author":"Loffredo","year":"2024","journal-title":"ACS Infect Dis"},{"issue":"1","key":"2026091109083881100_cit30","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1007\/s00018-025-05633-9","article-title":"Esc peptides and derivatives potentiate\nthe activity\nof CFTR with gating defects and display antipseudomonal activity in\ncystic fibrosis-like lung disease","volume":"82","author":"Ferrera","year":"2025","journal-title":"Cell. Mol.\nLife Sci."},{"key":"2026091109083881100_cit31","doi-asserted-by":"publisher","first-page":"234","DOI":"10.3390\/antibiotics11020234","article-title":"The Antimicrobial\nPeptide Esc(1-21) Synergizes with Colistin in Inhibiting the Growth\nand in Killing Multidrug Resistant Acinetobacter baumannii Strains","volume":"11","author":"Sacco","year":"2022","journal-title":"Antibiotics (Basel)"},{"key":"2026091109083881100_cit32","doi-asserted-by":"publisher","first-page":"2773","DOI":"10.1007\/s00018-013-1291-7","article-title":"Esculentin(1-21),\nan amphibian skin membrane-active peptide with potent activity on\nboth planktonic and biofilm cells of the bacterial pathogen Pseudomonas\naeruginosa","volume":"70","author":"Luca","year":"2013","journal-title":"Cell. Mol. Life Sci."},{"key":"2026091109083881100_cit33","doi-asserted-by":"publisher","first-page":"656","DOI":"10.3390\/antibiotics11050656","article-title":"Derivatives\nof Esculentin-1 Peptides as Promising Candidates\nfor Fighting Infections from Escherichia coli O157:H7","volume":"11","author":"Scotti","year":"2022","journal-title":"Antibiotics (Basel)"},{"key":"2026091109083881100_cit34","doi-asserted-by":"publisher","first-page":"1155","DOI":"10.2174\/0929866525666181101104649","article-title":"Esculentin-1a Derived Antipseudomonal Peptides: Limited\nInduction of Resistance and Synergy with Aztreonam","volume":"25","author":"Casciaro","year":"2019","journal-title":"Protein Pept Lett."},{"issue":"10","key":"2026091109083881100_cit35","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00574-21","article-title":"Evolutionary Trajectories toward\nCeftazidime-Avibactam Resistance in Klebsiella pneumoniae Clinical\nIsolates","volume":"65","author":"Carattoli","year":"2021","journal-title":"Antimicrob. Agents Chemother."},{"key":"2026091109083881100_cit36","unstructured":"Quest Graph LD50\nCalculator; AAT\nBioquest, Inc., 2026."},{"key":"2026091109083881100_cit37","doi-asserted-by":"publisher","first-page":"1271153","DOI":"10.3389\/fchem.2023.1271153","article-title":"The antimicrobial peptide Esc(1-21)-1c\nincreases susceptibility of Pseudomonas aeruginosa to conventional\nantibiotics by decreasing the expression of the MexAB-OprM efflux\npump","volume":"11","author":"Cane","year":"2023","journal-title":"Front Chem."},{"key":"2026091109083881100_cit38","doi-asserted-by":"publisher","first-page":"868","DOI":"10.1080\/22221751.2020.1754133","article-title":"Colistin and its role in the Era of antibiotic resistance:\nan extended review (2000\u20132019)","volume":"9","author":"El-Sayed Ahmed","year":"2020","journal-title":"Emerg\nMicrobes Infect"},{"key":"2026091109083881100_cit39","doi-asserted-by":"publisher","first-page":"100104","DOI":"10.1016\/j.pharmr.2025.100104","article-title":"Synergistic combinations\nof antimicrobial\npeptides and conventional antibiotics: A strategy to delay resistance\nemergence in World Health Organization priority bacteria","volume":"78","author":"Roque-Borda","year":"2026","journal-title":"Pharmacol Rev."},{"key":"2026091109083881100_cit40","doi-asserted-by":"publisher","first-page":"374","DOI":"10.3390\/antibiotics14040374","article-title":"Frog Skin Peptides Hylin-a1, AR-23,\nand RV-23: Promising Tools Against Carbapenem-Resistant Escherichia\ncoli and Klebsiella pneumoniae Infections","volume":"14","author":"Chianese","year":"2025","journal-title":"Antibiotics\n(Basel)"},{"key":"2026091109083881100_cit41","doi-asserted-by":"publisher","first-page":"3906","DOI":"10.1128\/AAC.00092-15","article-title":"Antibiofilm\npeptides increase the\nsusceptibility of carbapenemase-producing Klebsiella pneumoniae clinical\nisolates to beta-lactam antibiotics","volume":"59","author":"Ribeiro","year":"2015","journal-title":"Antimicrob.\nAgents Chemother."},{"key":"2026091109083881100_cit42","doi-asserted-by":"publisher","first-page":"800","DOI":"10.1016\/j.bbamem.2015.12.027","article-title":"NMR structure\nand binding of esculentin-1a (1-21)NH2 and its diastereomer to lipopolysaccharide:\nCorrelation with biological functions","volume":"1858","author":"Ghosh","year":"2016","journal-title":"Biochim.\nBiophys. Acta"},{"key":"2026091109083881100_cit43","doi-asserted-by":"publisher","first-page":"2327","DOI":"10.1016\/j.bbamem.2017.09.009","article-title":"Membrane perturbing activities and\nstructural properties of the frog-skin derived peptide Esculentin-1a(1-21)NH(2)\nand its Diastereomer Esc(1-21)-1c: Correlation with their antipseudomonal\nand cytotoxic activity","volume":"1859","author":"Loffredo","year":"2017","journal-title":"Biochim Biophys Acta\nBiomembr"},{"key":"2026091109083881100_cit44","doi-asserted-by":"publisher","first-page":"808","DOI":"10.1016\/j.bbapap.2008.11.005","article-title":"Outer membrane\npermeability and antibiotic resistance","volume":"1794","author":"Delcour","year":"2009","journal-title":"Biochim.\nBiophys. Acta"},{"key":"2026091109083881100_cit45","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1128\/CMR.00117-14","article-title":"The challenge of efflux-mediated\nantibiotic resistance in Gram-negative bacteria","volume":"28","author":"Li","year":"2015","journal-title":"Clin Microbiol Rev."},{"issue":"1","key":"2026091109083881100_cit46","doi-asserted-by":"publisher","DOI":"10.1128\/aac.01354-22","article-title":"Molecular\nCharacteristics of an NDM-4 and OXA-181 Co-Producing K51-ST16 Carbapenem-Resistant\nKlebsiella pneumoniae: Study of Its Potential Dissemination Mediated\nby Conjugative Plasmids and Insertion Sequences","volume":"67","author":"Zhang","year":"2023","journal-title":"Antimicrob. Agents Chemother."},{"key":"2026091109083881100_cit47","doi-asserted-by":"publisher","first-page":"1092556","DOI":"10.3389\/fmicb.2022.1092556","article-title":"beta-Lactam\npotentiators to re-sensitize resistant pathogens: Discovery, development,\nclinical use and the way forward","volume":"13","author":"Narendrakumar","year":"2022","journal-title":"Front. Microbiol."},{"key":"2026091109083881100_cit48","doi-asserted-by":"publisher","first-page":"1963","DOI":"10.1038\/s41564-025-02058-9","article-title":"Peptidoglycan-outer\nmembrane attachment generates periplasmic pressure to prevent lysis\nin Gram-negative bacteria","volume":"10","author":"Deghelt","year":"2025","journal-title":"Nat. Microbiol"},{"key":"2026091109083881100_cit49","doi-asserted-by":"publisher","first-page":"1569719","DOI":"10.3389\/fmicb.2025.1569719","article-title":"The inhibitory\npotential of three scorpion venom peptides\nagainst multidrug-resistant Klebsiella pnemoniae","volume":"16","author":"Giugliano","year":"2025","journal-title":"Front. Microbiol."},{"key":"2026091109083881100_cit50","doi-asserted-by":"publisher","first-page":"107054","DOI":"10.1016\/j.ijantimicag.2023.107054","article-title":"Efficacy of\nthe bee-venom antimicrobial\npeptide Osmin against sensitive and carbapenem-resistant Klebsiella\npneumoniae strains","volume":"63","author":"Jeon","year":"2024","journal-title":"Int. J. Antimicrob. Agents"},{"key":"2026091109083881100_cit51","doi-asserted-by":"publisher","first-page":"115377","DOI":"10.1016\/j.ejmech.2023.115377","article-title":"Antimicrobial peptides:\nStructure, mechanism, and modification","volume":"255","author":"Chen","year":"2023","journal-title":"Eur.\nJ. Med. 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