{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T18:02:47Z","timestamp":1790791367579,"version":"4.1.0"},"reference-count":42,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,7,7]],"date-time":"2022-07-07T00:00:00Z","timestamp":1657152000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002403","name":"Ministry of Education in Saudi Arabia","doi-asserted-by":"publisher","award":["442\/88"],"award-info":[{"award-number":["442\/88"]}],"id":[{"id":"10.13039\/501100002403","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Deanship of scientific research at Taibah University","award":["442\/88"],"award-info":[{"award-number":["442\/88"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibiotics"],"abstract":"<jats:p>Bacterial pneumonia is considered one of the most virulent diseases with high morbidity and mortality rates, especially in hospitalized patients. Moreover, bacterial resistance increased over the last decades which limited the therapy options to carbapenem antibiotics. Hence, the metallo-\u03b2-lactamase-producing bacteria were deliberated as the most deadly and ferocious infectious agents. Sulphadiazine-ZnO hybrids biological activity was explored in vitro and in vivo against metallo-\u03b2-lactamases (MBLs) producing Klebsiella pneumoniae. Docking studies against NDM-1 and IMP-1 MBLs revealed the superior activity of the 3a compound in inhibiting both MBLs enzymes in a valid reliable docking approach. The MBLs inhibition enzyme assay revealed the remarkable sulphadiazine-ZnO hybrids inhibitory effect against NDM-1 and IMP-1 MBLs. The tested compounds inhibited the enzymes both competitively and noncompetitively. Compound 3b-ZnO showed the highest antibacterial activity against the tested metallo-\u03b2-lactamase producers with an inhibition zone (IZ) diameter reaching 43 mm and a minimum inhibitory concentration (MIC) reaching 2 \u00b5g\/mL. Sulphadiazine-ZnO hybrids were tested for their in vitro cytotoxicity in a normal lung cell line (BEAS-2Bs cell line). Higher cell viability was observed with 3b-ZnO. Biodistribution of the sulphadiazine-ZnO hybrids in the lungs of uninfected rats revealed that both [124I]3a-ZnO and [124I]3b-ZnO hybrids remained detectable within the rats\u2019 lungs after 24 h of endotracheal aerosolization. Moreover, the residence duration in the lungs of [124I]3b-ZnO (t1\/2 4.91 h) was 85.3%. The histopathological investigations confirmed that compound 3b-ZnO has significant activity in controlling bacterial pneumonia infection in rats.<\/jats:p>","DOI":"10.3390\/antibiotics11070916","type":"journal-article","created":{"date-parts":[[2022,7,7]],"date-time":"2022-07-07T22:11:47Z","timestamp":1657231907000},"page":"916","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Novel 1,2,3-Triazole-sulphadiazine-ZnO Hybrids as Potent Antimicrobial Agents against Carbapenem Resistant Bacteria"],"prefix":"10.3390","volume":"11","author":[{"given":"Faizah S.","family":"Aljohani","sequence":"first","affiliation":[{"name":"Department of Chemistry, College of Science, Taibah University, Al-Madinah Al-Munawarah 30002, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8330-1738","authenticated-orcid":false,"given":"Nadjet","family":"Rezki","sequence":"additional","affiliation":[{"name":"Department of Chemistry, College of Science, Taibah University, Al-Madinah Al-Munawarah 30002, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7018-6654","authenticated-orcid":false,"given":"Mohamed R.","family":"Aouad","sequence":"additional","affiliation":[{"name":"Department of Chemistry, College of Science, Taibah University, Al-Madinah Al-Munawarah 30002, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0169-7738","authenticated-orcid":false,"given":"Mohamed","family":"Hagar","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Science, Alexandria University, Alexandria 21321, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Basant A.","family":"Bakr","sequence":"additional","affiliation":[{"name":"Department of Zoology, Faculty of Science, Alexandria University, Alexandria 21321, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0036-0482","authenticated-orcid":false,"given":"Marwa M.","family":"Shaaban","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6596-3156","authenticated-orcid":false,"given":"Bassma H.","family":"Elwakil","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratory Technology, Faculty of Applied Health Sciences Technology, Pharos University in Alexandria, Alexandria 21311, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"101826","DOI":"10.1016\/j.redox.2020.101826","article-title":"Antimicrobial effects of nitric oxide in murine models of Klebsiella pneumonia","volume":"39","author":"Wiegand","year":"2021","journal-title":"Redox Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1086\/533452","article-title":"Federal funding for the study of antimicrobial resistance in nosocomial pathogens: No ESKAPE","volume":"197","author":"Rice","year":"2008","journal-title":"J. Infect. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e00604","DOI":"10.1016\/j.btre.2021.e00604","article-title":"Antibiotic resistance: Global health crisis and metagenomics","volume":"29","author":"Yadav","year":"2021","journal-title":"Biotechnol. Rep."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Glover, R.E., Petticrew, M.P., Mays, N.B., and Thompson, C. (2022). How pharmaceutical and diagnostic stakeholders construct policy solutions to a public health \u2018crisis\u2019: An analysis of submissions to a United Kingdom House of Commons inquiry into antimicrobial resistance. Crit. Public Health, 1\u201310.","DOI":"10.1080\/09581596.2022.2026296"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"116624","DOI":"10.1016\/j.envpol.2021.116624","article-title":"\u03b2-Lactam antibiotics and antibiotic resistance in Asian lakes and rivers: An overview of contamination, sources and detection methods","volume":"275","author":"Ana","year":"2021","journal-title":"Environ. Pollut."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"104386","DOI":"10.1016\/j.bioorg.2020.104386","article-title":"Design, synthesis, biological evaluation and in silico studies of certain aryl sulfonyl hydrazones conjugated with 1, 3-diaryl pyrazoles as potent metallo-\u03b2-lactamase inhibitors","volume":"105","author":"Shaaban","year":"2020","journal-title":"Bioorg. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e28","DOI":"10.1016\/S1473-3099(20)30868-9","article-title":"The urgent need for metallo-\u03b2-lactamase inhibitors: An unattended global threat","volume":"22","author":"Mojica","year":"2021","journal-title":"Lancet Infect. Dis."},{"key":"ref_8","first-page":"130","article-title":"Structure, function of serine and metallo-\u03b2-lactamases and their inhibitors","volume":"19","author":"Salahuddin","year":"2018","journal-title":"Curr. Protein Pept. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2242","DOI":"10.1038\/s41467-017-02339-w","article-title":"The mechanism of NDM-1-catalyzed carbapenem hydrolysis is distinct from that of penicillin or cephalosporin hydrolysis","volume":"8","author":"Feng","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"756","DOI":"10.2174\/1389450120666181217101812","article-title":"Recent review on subclass B1 metallo-\u03b2-lactamases inhibitors: Sword for antimicrobial resistance","volume":"20","author":"Kaushik","year":"2019","journal-title":"Curr. Drug Targets"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"113667","DOI":"10.1016\/j.ejmech.2021.113667","article-title":"Recent research and development of NDM-1 inhibitors","volume":"223","author":"Wang","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1001\/archinte.163.4.402","article-title":"Trimethoprim-sulfamethoxazole revisited","volume":"163","author":"Masters","year":"2003","journal-title":"Arch. Intern. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"719","DOI":"10.3390\/antibiotics11060719","article-title":"Efficacy of Trimethoprim\u2013Sulfamethoxazole in Combination with an Echinocandin as a First-Line Treatment Option for Pneumocystis Pneumonia: A Systematic Review and Meta-Analysis","volume":"11","author":"Hideo","year":"2022","journal-title":"Antibiotics"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Haseeb, A., Abourehab, M.A.S., Almalki, W.A., Almontashri, A.M., Bajawi, S.A., Aljoaid, A.M., Alsahabi, B.M., Algethamy, M., AlQarni, A., and Iqbal, M.S. (2022). Trimethoprim-Sulfamethoxazole (Bactrim) Dose Optimization in Pneumocystis jirovecii Pneumonia (PCP) Management: A Systematic Review. Int. J. Environ. Res. Public Health, 19.","DOI":"10.3390\/ijerph19052833"},{"key":"ref_15","unstructured":"Kalarikkal, N., Mohan, S., Oluwafemi, S.O., and Thomas, S. (2018). Characterization of Nanomaterials: Advances and Key Technologies, Woodhead Publishing."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"7787","DOI":"10.1039\/C5CS00041F","article-title":"Inorganic nanoparticles engineered to attack bacteria","volume":"44","author":"Miller","year":"2015","journal-title":"Chem. Soc. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/S0167-7012(03)00037-X","article-title":"Quantitative evaluation of antibacterial activities of metallic oxide powders (ZnO, MgO and CaO) by conductimetric assay","volume":"54","author":"Sawai","year":"2003","journal-title":"J. Microbiol. Methods"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"10466","DOI":"10.1021\/acsomega.0c00590","article-title":"NMR Characterization of the Influence of Zinc (II) Ions on the Structural and Dynamic Behavior of the New Delhi Metallo-\u03b2-Lactamase-1 and on the Binding with Flavonols as Inhibitors","volume":"5","author":"Oueslati","year":"2020","journal-title":"ACS Omega"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1099\/00222615-46-9-807","article-title":"The effect of zinc ions on the activity of metallo-beta-lactamases of Bacteroides fragilis","volume":"46","author":"Edwards","year":"1997","journal-title":"J. Med. Microbiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/j.msec.2019.02.004","article-title":"The fight against multidrug-resistant organisms: The role of ZnO crystalline defects","volume":"99","author":"Pascual","year":"2019","journal-title":"Mater. Sci. Eng. C"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Ali, S.G., Ansari, M.A., Alzohairy, M.A., Alomary, M.N., Jalal, M., AlYahya, S., Asiri, S.M.M., and Khan, H.M. (2020). Effect of biosynthesized ZnO nanoparticles on multi-drug resistant Pseudomonas aeruginosa. Antibiotics, 9.","DOI":"10.3390\/antibiotics9050260"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"26219","DOI":"10.1021\/acsami.7b09695","article-title":"Exploring new mechanisms for effective antimicrobial materials: Electric contact-killing based on multiple schottky barriers","volume":"9","author":"Reinosa","year":"2017","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1016\/S1466-6049(01)00197-0","article-title":"Influence of particle size on the antibacterial activity of zinc oxide","volume":"3","author":"Yamamoto","year":"2001","journal-title":"Int. J. Inorg. Mater."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"035004","DOI":"10.1088\/1468-6996\/9\/3\/035004","article-title":"Enhanced bioactivity of ZnO nanoparticles\u2014An antimicrobial study","volume":"9","author":"Padmavathy","year":"2008","journal-title":"Sci. Technol. Adv. Mater."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Aljohani, F.S., Rezki, N., Aouad, M.R., Elwakil, B.H., Hagar, M., Sheta, E., Mogahed, N.M.F.H., Bardaweel, S.K., and Hagras, N.A.-e. (2022). Synthesis, Characterization and Nanoformulation of Novel Sulfonamide-1, 2, 3-triazole Molecular Conjugates as Potent Antiparasitic Agents. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23084241"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1016\/j.bmcl.2016.02.007","article-title":"Captopril analogues as metallo-beta-lactamase inhibitors","volume":"26","author":"Yusof","year":"2016","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_27","first-page":"651","article-title":"FEZ-1 metallo-beta-lactamase from Legionella gormanii modelled with D-captopril","volume":"325","author":"Mercuri","year":"2003","journal-title":"J. Mol. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2282","DOI":"10.1039\/b802311e","article-title":"Structural basis for the broad-spectrum inhibition of metallo-\u03b2-lactamases by thiols","volume":"6","author":"Garau","year":"2008","journal-title":"Org. Biomol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1007\/s40820-015-0040-x","article-title":"Review on zinc oxide nanoparticles: Antibacterial activity and toxicity mechanism","volume":"7","author":"Sirelkhatim","year":"2015","journal-title":"Nano-Micro Lett."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.colsurfa.2014.05.057","article-title":"The contribution of zinc ions to the antimicrobial activity of zinc oxide","volume":"457","author":"Pasquet","year":"2014","journal-title":"Colloids Surf. A Physicochem. Eng. Asp."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2121","DOI":"10.1021\/nn800511k","article-title":"Comparison of the mechanism of toxicity of zinc oxide and cerium oxide nanoparticles based on dissolution and oxidative stress properties","volume":"2","author":"Xia","year":"2008","journal-title":"ACS Nano"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1128\/AAC.01335-15","article-title":"Structural Basis of Metallo-\u03b2-Lactamase Inhibition by Captopril Stereoisomers","volume":"60","author":"Brem","year":"2016","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"11362","DOI":"10.1021\/ja303579d","article-title":"New Delhi metallo-beta-lactamase: Structural insights into beta-lactam recognition and inhibition","volume":"134","author":"King","year":"2012","journal-title":"J. Am. Chem. Soc."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"8544","DOI":"10.1021\/acs.jmedchem.9b00911","article-title":"Bicyclic boronate VNRX-5133 inhibits metallo-and serine-\u03b2-lactamases","volume":"62","author":"Krajnc","year":"2019","journal-title":"J. Med. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1080\/14756366.2016.1222580","article-title":"Inhibition of Bacillus anthracis metallo-\u03b2-lactamase by compounds with hydroxamic acid functionality","volume":"31","author":"Kim","year":"2016","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.4155\/fmc.13.55","article-title":"Targeting metallo-\u03b2-lactamase enzymes in antibiotic resistance","volume":"5","author":"King","year":"2013","journal-title":"Future Med. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.2217\/nnm-2019-0467","article-title":"Novel Siwa propolis and colistin-integrated chitosan nanoparticles: Elaboration; in vitro and in vivo appraisal","volume":"15","author":"Elnaggar","year":"2020","journal-title":"Nanomedicine"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"McAlinden, K.D., Lu, W., Ferdowsi, P.V., Myers, S., Markos, J., Larby, J., Chia, C., Weber, H.C., Haug, G., and Eapen, M.S. (2021). Electronic cigarette aerosol is cytotoxic and increases ACE2 expression on human airway epithelial cells: Implications for SARS-CoV-2 (COVID-19). J. Clin. Med., 10.","DOI":"10.3390\/jcm10051028"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1002\/jgm.1472","article-title":"The ARRIVE guidelines, a welcome improvement to standards for reporting animal research","volume":"12","author":"Danos","year":"2010","journal-title":"J. Gene Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"5406","DOI":"10.1016\/j.biomaterials.2012.04.036","article-title":"Endothelial targeting of polymeric nanoparticles stably labeled with the PET imaging radioisotope iodine-124","volume":"33","author":"Simone","year":"2012","journal-title":"Biomaterials"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1128\/IAI.00559-09","article-title":"Absence of inflammation and pneumonia during infection with nonpigmented Yersinia pestis reveals a new role for the pgm locus in pathogenesis","volume":"78","author":"Anderson","year":"2010","journal-title":"Infect. Immun."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"111034","DOI":"10.1016\/j.biopha.2020.111034","article-title":"Outer membrane protein a in Acinetobacter baumannii induces autophagy through mTOR signaling pathways in the lung of SD rats","volume":"135","author":"Zhao","year":"2021","journal-title":"Biomed. Pharmacother."}],"container-title":["Antibiotics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-6382\/11\/7\/916\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:44:01Z","timestamp":1760139841000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-6382\/11\/7\/916"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,7]]},"references-count":42,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["antibiotics11070916"],"URL":"https:\/\/doi.org\/10.3390\/antibiotics11070916","relation":{},"ISSN":["2079-6382"],"issn-type":[{"value":"2079-6382","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,7]]}}}