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Due to increasing drug\u2010resistance of virulent pathogen such as <jats:italic>Gardnerella vaginalis<\/jats:italic> (<jats:italic>G. vaginalis<\/jats:italic>), more than half of BV patients suffer recurrence after antibotics treatment. Here, metastable iron sulfides (mFeS) act in a Gram\u2010dependent manner to kill bacteria, with the ability to counteract resistant <jats:italic>G. vaginalis<\/jats:italic> for BV treatment. With screening of iron sulfide minerals, metastable Fe<jats:sub>3<\/jats:sub>S<jats:sub>4<\/jats:sub> shows suppressive effect on bacterial growth with an order: Gram\u2010variable <jats:italic>G. vaginalis<\/jats:italic> &gt;Gram\u2010negative bacteria&gt;&gt; Gram\u2010positive bacteria. Further studies on mechanism of action (MoA) discover that the polysulfide species released from Fe<jats:sub>3<\/jats:sub>S<jats:sub>4<\/jats:sub> selectively permeate bacteria with thin wall and subsequently interrupt energy metabolism by inhibiting glucokinase in glycolysis, and is further synergized by simultaneously released ferrous iron that induces bactericidal damage. Such multiple MoAs enable Fe<jats:sub>3<\/jats:sub>S<jats:sub>4<\/jats:sub> to counteract <jats:italic>G. vaginalis<\/jats:italic> strains with metronidazole\u2010resistance and persisters in biofilm or intracellular vacuole, without developing new drug resistance and killing probiotic bacteria. The Fe<jats:sub>3<\/jats:sub>S<jats:sub>4<\/jats:sub> regimens successfully ameliorate BV with resistant <jats:italic>G. vaginalis<\/jats:italic> in mouse models and eliminate pathogens from patients suffering BV. Collectively, mFeS represent an antibacterial alternative with distinct MoA able to treat challenged BV and improve women health.<\/jats:p>","DOI":"10.1002\/advs.202104341","type":"journal-article","created":{"date-parts":[[2022,2,5]],"date-time":"2022-02-05T04:47:55Z","timestamp":1644036475000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":50,"title":["Metastable Iron Sulfides Gram\u2010Dependently Counteract Resistant <i>Gardnerella Vaginalis<\/i> for Bacterial Vaginosis Treatment"],"prefix":"10.1002","volume":"9","author":[{"given":"Ling","family":"Fang","sequence":"first","affiliation":[{"name":"CAS Engineering Laboratory for Nanozyme Institute of Biophysics Chinese Academy of Sciences  Beijing 100101 China"},{"name":"Institute of Translational Medicine Department of Pharmacology School of Medicine Yangzhou University  Yangzhou Jiangsu 225009 China"},{"name":"Xishan People's Hospital of Wuxi City  Wuxi Jiangsu 214105 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