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An increasing rate of infections caused by methicillin\u2010resistant <jats:italic>Staphylococcus\u00a0aureus<\/jats:italic> (<jats:styled-content style=\"fixed-case\">MRSA<\/jats:styled-content>) has necessitated the development of alternative agents. We previously reported that usnic acid (<jats:styled-content style=\"fixed-case\">UA<\/jats:styled-content>) has activity against <jats:styled-content style=\"fixed-case\">MRSA<\/jats:styled-content>; here, we report the effect of <jats:styled-content style=\"fixed-case\">UA<\/jats:styled-content> in combination with norfloxacin on the drug resistance of <jats:styled-content style=\"fixed-case\">MRSA<\/jats:styled-content> clinical isolates. We observed that the combination of <jats:styled-content style=\"fixed-case\">UA<\/jats:styled-content>\u2013norfloxacin significantly reduces the bacterial burden in mouse models infected with <jats:italic>S.\u00a0aureus<\/jats:italic>, without causing any detectable associated toxicity. Proteomic analysis indicated that <jats:styled-content style=\"fixed-case\">UA<\/jats:styled-content>\u2013norfloxacin induces oxidative stress within cells, which leads to membrane damage and inhibits metabolic activity and biosynthesis of peptidoglycan and fatty acids. Collectively, this study provides evidence that <jats:styled-content style=\"fixed-case\">UA<\/jats:styled-content> in combination with norfloxacin may be a potential candidate for development into a resistance\u2010modifying agent for the treatment of invasive <jats:styled-content style=\"fixed-case\">MRSA<\/jats:styled-content> infections.<\/jats:p>","DOI":"10.1002\/2211-5463.12650","type":"journal-article","created":{"date-parts":[[2019,5,3]],"date-time":"2019-05-03T11:49:57Z","timestamp":1556884197000},"page":"2025-2040","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Usnic acid modifies <scp>MRSA<\/scp> drug resistance through down\u2010regulation of proteins involved in peptidoglycan and fatty acid biosynthesis"],"prefix":"10.1002","volume":"9","author":[{"given":"Sneha","family":"Sinha","sequence":"first","affiliation":[{"name":"Molecular Bioprospection Department CSIR\u2010Central Institute of Medicinal and Aromatic Plants Lucknow India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivek Kumar","family":"Gupta","sequence":"additional","affiliation":[{"name":"Molecular Bioprospection Department CSIR\u2010Central Institute of Medicinal and Aromatic Plants Lucknow India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Parmanand","family":"Kumar","sequence":"additional","affiliation":[{"name":"Molecular Bioprospection Department CSIR\u2010Central Institute of Medicinal and Aromatic Plants Lucknow India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajiv","family":"Kumar","sequence":"additional","affiliation":[{"name":"Biotechnology Division CSIR\u2010Institute of Himalayan Bioresource Technology Palampur India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin","family":"Joshi","sequence":"additional","affiliation":[{"name":"Biotechnology Division CSIR\u2010Institute of Himalayan Bioresource Technology Palampur India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anirban","family":"Pal","sequence":"additional","affiliation":[{"name":"Molecular Bioprospection Department CSIR\u2010Central Institute of Medicinal and Aromatic Plants Lucknow India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahendra P.","family":"Darokar","sequence":"additional","affiliation":[{"name":"Molecular Bioprospection Department CSIR\u2010Central Institute of Medicinal and Aromatic Plants Lucknow India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,9,30]]},"reference":[{"key":"e_1_2_8_2_1","unstructured":"Centers for Disease Control and Prevention (CDC)(2013)Antibiotic resistance threats in the United States 2013. 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