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The limited number of established targets further restricts the identification of novel antibiotics to treat life-threatening MDR infections caused by <jats:italic>Staphylococcus aureus<\/jats:italic> strains. Therefore, novel targets for developing antibiotics are urgently required. In this study, we hypothesized that the G-quadruplex (G4)-binding ligands can be used as novel antibiotics as their binding can possibly downregulate\/block the expression of vital genes.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>To test this, first we screened the antibiotic properties of representative G4-binding ligands against hypervirulent and MDR <jats:italic>S. aureus<\/jats:italic> USA300 and determined the in vitro and in vivo antibacterial activity; and proposed the mechanism of action by applying various microbiological, infection, microscopic, and biophysicochemical techniques.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Herein, among screened G4-binding ligands, N-methyl mesoporphyrin IX (NMM) showed the highest antibacterial activity against <jats:italic>S. aureus<\/jats:italic> USA300. NMM exhibited a minimum inhibitory concentration (MIC) of 5\u00a0\u03bcM against <jats:italic>S. aureus<\/jats:italic> USA300, impacting cell division and the cell wall by repressing the expressions of genes in the division cell wall (<jats:italic>dcw<\/jats:italic>) gene cluster. Genome-wide bioinformatics analysis of G4 motifs and their mapping on <jats:italic>S. aureus<\/jats:italic> genome, identified the presence of G4-motif in the promoter of <jats:italic>mraZ<\/jats:italic>, a conserved master regulator of the <jats:italic>dcw<\/jats:italic> cluster regulating the coordinated cell division and cell wall synthesis. Physicochemical assessments using UV\u2013visible, circular dichroism, and nuclear magnetic resonance spectroscopy confirmed that the\u00a0G4-motif present in the <jats:italic>mraZ<\/jats:italic> promoter formed an\u00a0intramolecular parallel G4 structure, interacting with NMM. In vivo reporter followed by coupled in vitro transcription\/translation (IVT) assays confirmed the role of <jats:italic>mraZ<\/jats:italic> G4 as a target interacting NMM to impose extreme antibacterial activity against both the gram-positive and -negative bacteria. In-cell and in vivo validation of NMM using RAW264.7 cells and <jats:italic>Galleria mellonella<\/jats:italic>; respectively, demonstrated that NMM exhibited superior antibiotic activity compared to well-established antibiotics, with no observed cytotoxicity.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>In summary, the current study identified NMM as a broad-spectrum potent antibacterial agent and elucidated its plausible mechanism of action primarily by targeting G4-motif in the <jats:italic>mraZ<\/jats:italic> promoter of the <jats:italic>dcw<\/jats:italic> gene cluster.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s12929-024-01109-3","type":"journal-article","created":{"date-parts":[[2025,2,5]],"date-time":"2025-02-05T00:02:25Z","timestamp":1738713745000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Targeting the G-quadruplex as a novel strategy for developing antibiotics against hypervirulent drug-resistant Staphylococcus aureus"],"prefix":"10.1186","volume":"32","author":[{"given":"Maria","family":"Sultan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Razzaq","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joohyun","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shreyasi","family":"Das","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shrute","family":"Kannappan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinod Kumar","family":"Subramani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanki","family":"Yoo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Truc","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hye-Ra","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akhilesh K.","family":"Chaurasia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2515-8894","authenticated-orcid":false,"given":"Kyeong Kyu","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,2,5]]},"reference":[{"key":"1109_CR1","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1111\/j.1574-695X.2012.00937.x","volume":"65","author":"LR Thurlow","year":"2012","unstructured":"Thurlow LR, Joshi GS, Richardson AR. 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