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Structurally diverse naphthoquinones (NQs) including menadione (\u2212CH<jats:sub>3<\/jats:sub> group at C2) exhibit substantial antimicrobial activities against multidrug\u2010resistant (MDR) pathogens. We explored the combinations of menadione with antibiotic ciprofloxacin or ampicillin against <jats:italic>Staphylococcus aureus<\/jats:italic> and its biofilms. We found an additive (0.5&lt;FICI<jats:inline-graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"graphic\/cmdc202300328-math-0001.png\" xlink:title=\"urn:x-wiley:18607179:media:cmdc202300328:cmdc202300328-math-0001\"\/>\n1.0) and synergistic (FICI\u22640.5) effect of menadione with ciprofloxacin and ampicillin, respectively. High reactive oxygen species (ROS) activity and inhibition of biofilm formation (&gt;90\u2009%) were also observed. However, preformed biofilms were not affected. Dent formation was also evident in <jats:italic>S. aureus<\/jats:italic> treated with the test compounds. The structure\u2010function relationship (SFR) of NQs was used to determine and predict their activity pattern against pathogens. Analysis of 10 structurally distinct NQs revealed that the compounds with \u2212Cl, \u2212Br, \u2212CH<jats:sub>3<\/jats:sub>, or \u2212OH groups displayed the lowest MICs (32\u2013256\u2005\u03bcg\/mL). Furthermore, 1,4\u2010NQs possessing a halogen or \u2212CH<jats:sub>3<\/jats:sub> moiety showed elevated ROS activity, whereas molecules with an \u2212OH group affected cell integrity. Improved activity of antimicrobial combinations and SFR approaches are significant in antimicrobial therapies.<\/jats:p>","DOI":"10.1002\/cmdc.202300328","type":"journal-article","created":{"date-parts":[[2023,10,24]],"date-time":"2023-10-24T16:25:27Z","timestamp":1698164727000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["Synergistic and Additive Effects of Menadione in Combination with Antibiotics on Multidrug\u2010Resistant <i>Staphylococcus aureus<\/i>: Insights from Structure\u2010Function Analysis of Naphthoquinones"],"prefix":"10.1002","volume":"18","author":[{"given":"Nishigandha S.","family":"Mone","sequence":"first","affiliation":[{"name":"Department of Microbiology Savitribai Phule Pune University  Pune, Maharashtra 411007 India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sahil","family":"Syed","sequence":"additional","affiliation":[{"name":"Department of Microbiology Savitribai Phule Pune University  Pune, Maharashtra 411007 India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Palanisamy","family":"Ravichandiran","sequence":"additional","affiliation":[{"name":"Department of Energy Storage\/Conversion Engineering (BK21 FOUR) of Graduate School, Hydrogen and Fuel Cell Research Center Jeonbuk National University  Jeonju, Jeollabuk-do 54896 Republic of Korea"},{"name":"Department of Life Science Jeonbuk National University  Jeonju, Jeollabuk-do 54896 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ekta E.","family":"Kamble","sequence":"additional","affiliation":[{"name":"Department of Microbiology Savitribai Phule Pune University  Pune, Maharashtra 411007 India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karishma R.","family":"Pardesi","sequence":"additional","affiliation":[{"name":"Department of Microbiology Savitribai Phule Pune University  Pune, Maharashtra 411007 India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunita","family":"Salunke\u2010Gawali","sequence":"additional","affiliation":[{"name":"Department of Chemistry Savitribai Phule Pune University  Pune, Maharashtra m 411007 India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mansi","family":"Rai","sequence":"additional","affiliation":[{"name":"Department of Microbiology Central University of Rajasthan Ajmer  Rajasthan 305817 India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ajay","family":"Vikram Singh","sequence":"additional","affiliation":[{"name":"Department of Chemical and Product Safety German Federal Institute (BfR)  Max-Dohrn-Str. 8\u201310 10589 Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarada","family":"Prasad Dakua","sequence":"additional","affiliation":[{"name":"Department of Surgery Hamad Medical Corporation (HMC)  Doha 3050 Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Byung\u2010Hyun","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Biochemistry Jeonbuk National University Medical School  567 Baekje-daero, Deokjin-gu Jeonju-si, Jeollabuk-do 54896 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5707-3361","authenticated-orcid":false,"given":"Dong Jin","family":"Yoo","sequence":"additional","affiliation":[{"name":"Department of Energy Storage\/Conversion Engineering (BK21 FOUR) of Graduate School, Hydrogen and Fuel Cell Research Center Jeonbuk National University  Jeonju, Jeollabuk-do 54896 Republic of Korea"},{"name":"Department of Life Science Jeonbuk National University  Jeonju, Jeollabuk-do 54896 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Surekha K.","family":"Satpute","sequence":"additional","affiliation":[{"name":"Department of Microbiology Savitribai Phule Pune University  Pune, Maharashtra 411007 India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,11,10]]},"reference":[{"key":"e_1_2_10_1_1","first-page":"1","volume-title":"The Review on Antimicrobial Resistance.","author":"O'Neill J.","year":"2014"},{"key":"e_1_2_10_2_1","first-page":"277","volume":"40","author":"Ventola C. 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