{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:00:55Z","timestamp":1785420055833,"version":"3.56.0"},"reference-count":57,"publisher":"American Society for Microbiology","issue":"4","license":[{"start":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T00:00:00Z","timestamp":1775520000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T00:00:00Z","timestamp":1775520000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Microbiol Spectr"],"published-print":{"date-parts":[[2026,4,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      The New Delhi metallo-\u03b2-lactamase-producing\n                      <jats:italic toggle=\"yes\">Klebsiella pneumoniae<\/jats:italic>\n                      (NDM-Kp) strain is a high-risk pathogen responsible for many multidrug-resistant (MDR) infections worldwide, particularly in healthcare settings. The scarcity of effective metallo-\u03b2-lactamase (MBL) inhibitors highlights the urgent need for novel therapeutic strategies to combat this threat. In this study, we evaluated the synergistic effects of ceftriaxone (CRO) with the \u03b2-lactamase inhibitor BLI-489, aiming to restore the efficacy of cephalosporins against NDM-\n                      <jats:italic toggle=\"yes\">Kp<\/jats:italic>\n                      strains. The CRO\/BLI-489 exhibited significant synergistic activity\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      , as indicated by a fractional inhibitory concentration index (FICI) of 0.25. The combination significantly reduced the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against NDM-\n                      <jats:italic toggle=\"yes\">Kp<\/jats:italic>\n                      . This combination also inhibited biofilm formation. Hemolysis assays revealed that the hemolytic activity was significantly lower after treatment with CRO\/BLI-489 compared to that recorded after treatment with each compound alone. This finding indicated that the combination treatment has higher biocompatibility and retains antimicrobial efficacy. Molecular dynamics (MD) simulations revealed that the synergistic antibacterial effect of the CRO\/BLI-489 is mediated by interactions involving coordination with Zn\n                      <jats:sup>2+<\/jats:sup>\n                      ions in the catalytic site of the MBL enzyme. These results suggest that the combination can overcome MBL-mediated resistance mechanisms.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>The global spread of NDM-Kp poses a major challenge to healthcare systems because of the scarcity of effective treatment options. In response to the urgent need for new therapeutic strategies, this study explores the CRO\/BLI-489 as a promising alternative for overcoming MBL-mediated resistance. Although not yet an established therapy, this approach demonstrates the potential to restore cephalosporin efficacy, inhibit biofilm formation, and reduce cytotoxicity. These results offer valuable insights that may guide the development of future treatments for infections caused by multidrug-resistant pathogens. Our findings underscore the importance of further preclinical and clinical studies to validate this strategy and contribute to the global effort against antibiotic resistance.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/spectrum.01575-25","type":"journal-article","created":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T14:00:25Z","timestamp":1771941625000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["Synergistic effects of ceftriaxone combined with BLI-489 against NDM-producing\n                    <i>Klebsiella pneumoniae<\/i>"],"prefix":"10.1128","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-7618-233X","authenticated-orcid":false,"given":"Nathalia da Silva","family":"Damaceno","sequence":"first","affiliation":[{"name":"Federal University of Grande Dourados (UFGD), Research in Health Science Laboratory","place":["Dourados, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalia Monteiro Lins","family":"Freire","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00dna7t83","id-type":"ROR","asserted-by":"publisher"}],"name":"Federal University of Alagoas (UFAL), Research Group on Therapeutic Strategies, Institute of Chemistry and Biotechnology","place":["Macei\u00f3, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariana Carvalho","family":"Sturaro","sequence":"additional","affiliation":[{"name":"Federal University of Grande Dourados (UFGD), Research in Health Science Laboratory","place":["Dourados, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gleyce Hellen de Almeida","family":"de Souza","sequence":"additional","affiliation":[{"name":"Federal University of Grande Dourados (UFGD), Research in Health Science Laboratory","place":["Dourados, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Izadora Dillis","family":"Faccin","sequence":"additional","affiliation":[{"name":"Federal University of Grande Dourados (UFGD), Research in Health Science Laboratory","place":["Dourados, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0913-768X","authenticated-orcid":true,"given":"Ana Cristina","family":"Gales","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Internal Medicine, Federal University of S\u00e3o Paulo (UNIFESP), Laborat\u00f3rio Alerta, Paulista School of Medicine","place":["S\u00e3o Paulo, Brazil"]},{"name":"Antimicrobial Resistance Institute of S\u00e3o Paulo","place":["S\u00e3o Paulo, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thiago Mendon\u00e7a","family":"de Aquino","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00dna7t83","id-type":"ROR","asserted-by":"publisher"}],"name":"Federal University of Alagoas (UFAL), Research Group on Therapeutic Strategies, Institute of Chemistry and Biotechnology","place":["Macei\u00f3, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2367-0915","authenticated-orcid":true,"given":"Simone","family":"Simionatto","sequence":"additional","affiliation":[{"name":"Federal University of Grande Dourados (UFGD), Research in Health Science Laboratory","place":["Dourados, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(24)01867-1"},{"key":"e_1_3_2_3_2","unstructured":"Sati H Tacconelli E Carrara E Savoldi A Garcia-Vello P Zignol M Cameron A. 2024. 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