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

Abstract

Bacterial vaginosis (BV) is the most common vaginal infection found inwomen 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 Fe 3 S 4 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 Fe 3 S 4 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 3 S 4 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 Fe 3 S 4 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.

Metastable Iron Sulfides: A Versatile Antibacterial Candidate with Multiple Mechanisms against Bacterial Resistance

“…The ability to release polysulfide and ferrous iron is closely related to the crystal phase of mFeSs. We found that Fe 3 S 4 showed the best efficiency, followed by Fe 7 S 8 and Fe 1– x S, consistent with the energy barrier of the Fe–S bond . To accelerate the release process, we developed a facile decoction procedure inspired by Traditional Chinese Medicine, whereby mFeSs were mixed with distilled water in an autoclave at 121 °C for 15 min, with the resulting supernatant containing polysulfanes and ferrous iron collected and stored for antibacterial use.…”

“…In culture media, DADS-Fe 3 S 4 completely inhibited the growth of G. vaginalis and prevented regrowth after long incubation time (72 h or more) for ferrous iron and polysulfides quickly entering bacterial cytoplasm (Figure 6A,B), showing a MIC at 80 μM. 10 In contrast, although showing a MIC similar to that of G. vaginalis, metronidazole could not completely inhibit their growth. For the metronidazole-resistant strain of G. vaginalis, metronidazole showed no effect, but DADS-Fe 3 S 4 showed the same MIC as that for wild-type G. vaginalis.…”

“…(B) Fe–S bond length of typical iron sulfide minerals corresponding to A . Reproduced from ref with permission from the John Wiley Publishing Group, copyright 2022. (C) Types of iron sulfur clusters in proteins.…”

“…(E) Schematic of BV treatment with mFeSs against bacterial resistance. Reproduced from ref with permission from the John Wiley Publishing Group, copyright 2022.…”

Hexyl-Aminolevulinate Ethosomes: a Novel Antibiofilm Agent Targeting Zinc Homeostasis in Candida albicans

“… C. albicans biofilms without drug treatment served as a control group. Total RNA extraction, RNA-seq, and bioinformatic data collection were performed by Shanghai Personalbio (Shanghai, China) ( 48 ). Each group was analyzed in triplicate samples.…”