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Penicillin\u2010binding protein 2a (PBP2a) plays a crucial role in bacterial cell wall synthesis. In this work, 125 imidazole\u2010based tetrapeptides were rationally designed and evaluated in silico and experimentally. Molecular docking studies revealed binding energies from \u22126.6 to \u22124.0\u2009kcal\/mol against MRSA target. The six most promising compounds (\n                    <jats:bold>A\u2013F<\/jats:bold>\n                    ) were synthesized and screened against methicillin\u2010susceptible\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>S. aureus<\/jats:italic>\n                    <\/jats:styled-content>\n                    (MSSA), MRSA and VRSA. Compound\n                    <jats:bold>C<\/jats:bold>\n                    showed the most promising antibacterial analogue with minimum inhibitory concentration (MIC) of 29.8\u2009\u00b1\u20094.2\u2009\u03bcg\/mL among the analogues. Time\u2010kill assays demonstrated bactericidal activity against MSSA and MRSA and bacteriostatic activity against VRSA. All compounds showed &lt;\u20095% haemolysis, suggesting low toxicity. ADME predictions indicated favourable physicochemical properties and safety profiles. The molecular dynamics simulation (MDS) for compound\n                    <jats:bold>C<\/jats:bold>\n                    shows stable interactions with Ser403, Tyr446, Glu447, Ser462, Lys597, Ser598 and Thr600 key residues in the PBP2a active site. The DFT study confirms the stability of compound\n                    <jats:bold>C<\/jats:bold>\n                    in the PBP2a active site with a binding energy of \u221242.73\u2009kcal\/mol. Overall, compound\n                    <jats:bold>C<\/jats:bold>\n                    is a promising lead for anti\u2010\n                    <jats:italic>staphylococcal<\/jats:italic>\n                    drug development; however, the mechanism of action requires further experimental validation.\n                  <\/jats:p>","DOI":"10.1002\/psc.70098","type":"journal-article","created":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T09:30:47Z","timestamp":1777973447000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Rational Design and Biological Evaluation of Imidazole\u2010Based Tetrapeptides as Antibacterial Leads Against\n                    <scp>\n                      <i>Staphylococcus aureus<\/i>\n                    <\/scp>"],"prefix":"10.1002","volume":"32","author":[{"given":"Mohammed Sharif","family":"Shaik","sequence":"first","affiliation":[{"name":"Department of Chemistry, School of Applied Science and Humanities Vignan's Foundation for Science Technology and Research  Guntur Andhra Pradesh India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vidya Sagar","family":"Jerra","sequence":"additional","affiliation":[{"name":"Department of Chemistry, School of Applied Science and Humanities Vignan's Foundation for Science Technology and Research  Guntur Andhra Pradesh India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Balajee","family":"Ramachandran","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Physiology and Biophysics Boston University Chobanian and Avedisian School of Medicine  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9533-1299","authenticated-orcid":false,"given":"Srinivasadesikan","family":"Venkatesan","sequence":"additional","affiliation":[{"name":"Department of Chemistry, School of Applied Science and Humanities Vignan's Foundation for Science Technology and Research  Guntur Andhra Pradesh India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,5,5]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsinfecdis.3c00571"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsomega.2c04381"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci68834"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/iub.1289"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41579\u2010019\u20100288\u20100"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt1267"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/bip.20911"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.langmuir.3c00498"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.3390\/ph9040067"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcis.2024.01.123"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/psc.365"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamem.2006.04.006"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1177\/0022034516679973"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro1098"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1128\/aac.00453\u201011"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules24224173"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagen.2017.03.024"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1021\/bc500510c"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2015.10.015"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.5012\/bkcs.2014.35.9.2818"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1128\/spectrum.02247\u201022"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.3390\/md13053029"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573\u2010020\u201000135\u20108"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1039\/c7ra05601j"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd3591"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.21334"},{"key":"e_1_2_8_28_1","unstructured":"N.Schapin C.Navarro A.Bou andD. 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