Metastable Iron Sulfides Gram‐Dependently Counteract Resistant Gardnerella Vaginalis for Bacterial Vaginosis Treatment

Bacterial vaginosis (BV) is the most common vaginal infection found in women in the world. Due to increasing drug‐resistance of virulent pathogen such as Gardnerella vaginalis (G. vaginalis), more than half of BV patients suffer recurrence after antibotics treatment. Here, metastable iron sulfides (mFeS) act in a Gram‐dependent manner to kill bacteria, with the ability to counteract resistant G. vaginalis for BV treatment. With screening of iron sulfide minerals, metastable Fe3S4 shows suppressive effect on bacterial growth with an order: Gram‐variable G. vaginalis >Gram‐negative bacteria>> Gram‐positive bacteria. Further studies on mechanism of action (MoA) discover that the polysulfide species released from Fe3S4 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 Fe3S4 to counteract G. vaginalis strains with metronidazole‐resistance and persisters in biofilm or intracellular vacuole, without developing new drug resistance and killing probiotic bacteria. The Fe3S4 regimens successfully ameliorate BV with resistant G. vaginalis 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.

[1]  A. Ouwehand,et al.  Short communication: Characterization of vaginal fungal communities in healthy women and women with bacterial vaginosis (BV); a pilot study. , 2021, Microbial pathogenesis.

[2]  M. Otyepka,et al.  Silver Covalently Bound to Cyanographene Overcomes Bacterial Resistance to Silver Nanoparticles and Antibiotics , 2021, Advanced science.

[3]  Lizeng Gao,et al.  Oral Administration of Nanoiron Sulfide Supernatant for the Treatment of Gallbladder Stones with Chronic Cholecystitis , 2020 .

[4]  Yili Yang,et al.  Nano-decocted ferrous polysulfide coordinates ferroptosis-like death in bacteria for anti-infection therapy , 2020 .

[5]  I. Mysorekar,et al.  Gardnerella vaginalis promotes group B Streptococcus vaginal colonization, enabling ascending uteroplacental infection in pregnant mice. , 2020, American journal of obstetrics and gynecology.

[6]  L. Than,et al.  Vaginal microbiota and the potential of Lactobacillus derivatives in maintaining vaginal health , 2020, Microbial Cell Factories.

[7]  Suzannah M. Schmidt-Malan,et al.  Nanomaterial-based therapeutics for antibiotic-resistant bacterial infections , 2020, Nature Reviews Microbiology.

[8]  Maxwell Z. Wilson,et al.  A Dual-Mechanism Antibiotic Kills Gram-Negative Bacteria and Avoids Drug Resistance , 2020, Cell.

[9]  N. Gilbert,et al.  Gardnerella vaginalis as a Cause of Bacterial Vaginosis: Appraisal of the Evidence From in vivo Models , 2020, Frontiers in Cellular and Infection Microbiology.

[10]  J. H. van de Wijgert,et al.  Impact of oral metronidazole treatment on the vaginal microbiota and correlates of treatment failure , 2020, American journal of obstetrics and gynecology.

[11]  A. Okamoto,et al.  Biogenic Iron Sulfide Nanoparticles Enable Extracellular Electron Uptake in Sulfate-Reducing Bacteria. , 2019, Angewandte Chemie.

[12]  Lu-jin Li,et al.  Probiotics for the treatment of women with bacterial vaginosis: A systematic review and meta-analysis of randomized clinical trials. , 2019, European journal of pharmacology.

[13]  B. Faught,et al.  Characterization and Treatment of Recurrent Bacterial Vaginosis. , 2019, Journal of women's health.

[14]  Daniela Machado,et al.  Unveiling the role of Gardnerella vaginalis in polymicrobial Bacterial Vaginosis biofilms: the impact of other vaginal pathogens living as neighbors , 2019, The ISME Journal.

[15]  Lizeng Gao,et al.  Iron oxide nanozyme suppresses intracellular Salmonella Enteritidis growth and alleviates infection in vivo , 2018, Theranostics.

[16]  Xingfa Gao,et al.  Converting organosulfur compounds to inorganic polysulfides against resistant bacterial infections , 2018, Nature Communications.

[17]  J. Parker,et al.  Inhibition of sialidase activity and cellular invasion by the bacterial vaginosis pathogen Gardnerella vaginalis , 2018, Archives of Microbiology.

[18]  X. Qu,et al.  Enzyme Mimicry for Combating Bacteria and Biofilms. , 2018, Accounts of chemical research.

[19]  Paul Stoodley,et al.  Targeting microbial biofilms: current and prospective therapeutic strategies , 2017, Nature Reviews Microbiology.

[20]  S. Witkin,et al.  Why do lactobacilli dominate the human vaginal microbiota? , 2017, BJOG : an international journal of obstetrics and gynaecology.

[21]  M. Vaneechoutte,et al.  The presence of the putative Gardnerella vaginalis sialidase A gene in vaginal specimens is associated with bacterial vaginosis biofilm , 2017, PloS one.

[22]  Tikam Chand Dakal,et al.  Mechanistic Basis of Antimicrobial Actions of Silver Nanoparticles , 2016, Frontiers in microbiology.

[23]  Yong Li,et al.  Nanocatalysts promote Streptococcus mutans biofilm matrix degradation and enhance bacterial killing to suppress dental caries in vivo. , 2016, Biomaterials.

[24]  P. Girguis,et al.  What Do We Really Know about the Role of Microorganisms in Iron Sulfide Mineral Formation? , 2016, Front. Earth Sci..

[25]  Daniela Machado,et al.  Bacterial Vaginosis Biofilms: Challenges to Current Therapies and Emerging Solutions , 2016, Front. Microbiol..

[26]  Berk Hess,et al.  GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers , 2015 .

[27]  J. Mckinney,et al.  Targeting bacterial central metabolism for drug development. , 2014, Chemistry & biology.

[28]  J. Schwebke,et al.  Role of Gardnerella vaginalis in the pathogenesis of bacterial vaginosis: a conceptual model. , 2014, The Journal of infectious diseases.

[29]  J. A. Lambert,et al.  Longitudinal Analysis of Vaginal Microbiome Dynamics in Women with Recurrent Bacterial Vaginosis: Recognition of the Conversion Process , 2013, PloS one.

[30]  D. Alcendor,et al.  Evidence for Gardnerella vaginalis uptake and internalization by squamous vaginal epithelial cells: implications for the pathogenesis of bacterial vaginosis. , 2012, Microbes and infection.

[31]  A. T. Vasconcelos,et al.  Common ancestry of iron oxide- and iron-sulfide-based biomineralization in magnetotactic bacteria , 2011, The ISME Journal.

[32]  Arthur J. Olson,et al.  AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading , 2009, J. Comput. Chem..

[33]  D. Rees,et al.  ABC transporters: the power to change , 2009, Nature Reviews Molecular Cell Biology.

[34]  M. Falagas,et al.  Probiotics for the treatment of women with bacterial vaginosis , 2007 .

[35]  L. Benning,et al.  Greigite: a true intermediate on the polysulfide pathway to pyrite , 2007, Geochemical transactions.

[36]  G. Luther,et al.  Chemistry of iron sulfides. , 2007, Chemical reviews.

[37]  R. Frankel,et al.  Magnetosome formation in prokaryotes , 2004, Nature Reviews Microbiology.

[38]  M. Pelletier,et al.  The phosphoenolpyruvate:sugar phosphotransferase system of oral streptococci and its role in the control of sugar metabolism. , 1997, FEMS microbiology reviews.

[39]  D. Vaughan,et al.  Synthesis and Rietveld crystal structure refinement of mackinawite, tetragonal FeS , 1995, Mineralogical Magazine.

[40]  A. Becke.  Density-functional thermochemistry. III. The role of exact exchange , 1993 .

[41]  J. Costerton,et al.  Gardnerella vaginalis has a gram-positive cell-wall ultrastructure and lacks classical cell-wall lipopolysaccharide. , 1989, Journal of medical microbiology.

[42]  G. A. Petersson,et al.  A complete basis set model chemistry. I. The total energies of closed‐shell atoms and hydrides of the first‐row elements , 1988 .

[43]  R. Zbořil,et al.  Bacterial resistance to silver nanoparticles and how to overcome it , 2017, Nature Nanotechnology.

[44]  G. Schneider.  Antimicrobial silver nanoparticles – regulatory situation in the European Union , 2017 .

[45]  R. A. KtJNKLE,et al.  Infectious disease. , 2015, Clinical privilege white paper.

[46]  L. Mosca,et al.  Effectiveness of Lactobacillus-containing vaginal tablets in the treatment of symptomatic bacterial vaginosis. , 2009, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[47]  G L Lautenbach,et al.  Women's health. , 1999, Rheumatic diseases clinics of North America.