{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T05:55:00Z","timestamp":1781848500208,"version":"3.54.5"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T00:00:00Z","timestamp":1781827200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:p>\n                    <jats:italic>Staphylococcus aureus<\/jats:italic>\n                    , especially methicillin-resistant\n                    <jats:italic>S. aureus<\/jats:italic>\n                    (MRSA), poses a severe threat to human health due to the limited efficacy of traditional antibiotics and the rapid emergence of drug resistance. Quaternary ammonium compounds (QACs) are promising antibacterial agents with a membrane-disruptive mechanism that is less prone to inducing resistance. Herein, a series of novel phthalazine-derived QACs (\n                    <jats:bold>2a<\/jats:bold>\n                    \u2013\n                    <jats:bold>2v<\/jats:bold>\n                    ) were designed, synthesized, and evaluated for their antibacterial activities. The structure-activity relationship (SAR) analysis revealed that the length of\n                    <jats:italic>N<\/jats:italic>\n                    -alkyl substituent significantly affected antibacterial potency, with compound\n                    <jats:bold>2n<\/jats:bold>\n                    emerging as the lead compound. Compound\n                    <jats:bold>2n<\/jats:bold>\n                    exhibited broad-spectrum antibacterial activity against\n                    <jats:italic>S. aureus<\/jats:italic>\n                    , MRSA,\n                    <jats:italic>Streptococcus pneumoniae<\/jats:italic>\n                    , and\n                    <jats:italic>Klebsiella pneumoniae<\/jats:italic>\n                    , with MIC values of 2 \u03bcg\/mL. It showed rapid bactericidal activity, low hemolysis (HC\n                    <jats:sub>50<\/jats:sub>\n                    &amp;gt; 64 \u03bcg\/mL), minimal resistance evolution, and excellent stability in physiological salts and against proteolytic enzymes, with certain concentration-dependent effects on biofilm. Mechanistic studies revealed that compound\n                    <jats:bold>2n<\/jats:bold>\n                    exerts antibacterial activity via triggering bacterial membrane damage, which was verified by multiple phenotypic results, including Gram staining alteration, increased extracellular AKP activity, cell membrane depolarization, intracellular protein and nucleic acid leakage, as well as morphological observations from SEM and DAPI\/PI staining. Molecular docking and competitive displacement assays indicated that compound\n                    <jats:bold>2n<\/jats:bold>\n                    may bind to bacterial DNA, which is presumed to be a potential auxiliary antibacterial mechanism. These findings suggest phthalazine-derived QACs are promising and compound\n                    <jats:bold>2n<\/jats:bold>\n                    has great potential for further development to combat drug-resistant bacterial infections.\n                  <\/jats:p>","DOI":"10.3389\/fmicb.2026.1864148","type":"journal-article","created":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T05:48:25Z","timestamp":1781848105000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Phthalazine-based quaternary ammonium salts: synthesis, biological evaluation and membrane-targeting mechanism against Staphylococcus aureus"],"prefix":"10.3389","volume":"17","author":[{"given":"Wenwen","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Neurology, Weifang People's Hospital, The First Clinical Hospital of Shandong Second Medical University, Weifang","place":["Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiling","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Weifang People's Hospital, The First Clinical Hospital of Shandong Second Medical University, Weifang","place":["Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong","family":"Xiao","sequence":"additional","affiliation":[{"name":"Clinical Laboratory, Weifang People's Hospital, The First Clinical Hospital of Shandong Second Medical University, Weifang","place":["Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wang","family":"Xin","sequence":"additional","affiliation":[{"name":"Pediatric Surgery Department, Weifang People's Hospital, The First Clinical Hospital of Shandong Second Medical University, Weifang","place":["Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baobao","family":"Meng","sequence":"additional","affiliation":[{"name":"Neurosurgery Department, Weifang People's Hospital, The First Clinical Hospital of Shandong Second Medical University, Weifang","place":["Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guifang","family":"Zhai","sequence":"additional","affiliation":[{"name":"Neurosurgery Department, Weifang People's Hospital, The First Clinical Hospital of Shandong Second Medical University, Weifang","place":["Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Weifang People's Hospital, The First Clinical Hospital of Shandong Second Medical University, Weifang","place":["Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"7641","DOI":"10.2147\/IDR.S428103","article-title":"Methicillin resistant Staphylococcus aureus: molecular mechanisms underlying drug resistance development and novel strategies to combat","volume":"16","author":"Abebe","year":"2023","journal-title":"Infect. 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