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

Abstract

Conspectus Bacterial infections pose an ongoing threat to global human health, an issue of growing urgency due to the emergence of resistance against many currently available antibiotics. Recently, the World Health Organization (WHO) launched a global appeal for the development of novel antibiotics to combat this issue. Ideal antibiotics should possess specific antibacterial effects, without causing resistance. However, the discovery of different antibiotics is lagging the development of drug-resistant bacteria. Many newly developed antibiotics not only are rapidly resisted by bacteria but also are ineffective against persistent bacteria embedded in biofilms and host cells. To tackle these challenges, innovative concepts and approaches are required for the discovery of novel antibacterial candidates. Agents for use against pathogenic bacteria were developed long before the discovery of antibiotics. For 3000 years, garlic has been considered an efficient antibacterial compound, utilized to prevent and treat bacterial infection worldwide, although the specific mechanisms remain unclear. Modern research shows that sulfur-containing chemicals are the primary active constituents of garlic and play key roles in its inherent antimicrobial activity, such as diallyl disulfide (DADS) and diallyl trisulfide (DATS). In contrast, inorganic sulfides for antibacterial use have not been deeply studied. It has been well-known that iron sulfides are an essential part of the geochemical and biological sulfur cycles. Both stable and metastable iron sulfides can be formed under abiotic sediment conditions and biotic process. In particular, certain bacteria species growth need iron sulfide as nutrient source or produce iron sulfide. In addition, iron sulfur clusters as special metastable iron sulfide take part in many important metabolic pathways in most organisms. These physicochemical and biological properties inspire us that iron sulfides are a type of valuable material for investigation and utilization. Below we will introduce a new antibacterial candidate based on iron sulfides, which kill bacteria via multiple mechanisms of action (MoAs). We will first discuss the types of iron sulfides with inherent antibacterial activity, i.e., metastable species that can release iron ions and polysulfides in aqua. The intrinsic properties of iron sulfides and released iron and polysulfides are analyzed in regard to antibacterial effects under different physiological conditions. In particular, ferrous ion–polysulfide synergized ferroptosis-like death is proposed to kill bacteria with broad spectrum and selectivity. In addition, the versatile MoAs enable metastable iron sulfides (mFeSs) to kill resistant bacteria, eradicate biofilms, and suppress intracellular persistent species without causing new drug resistance. Importantly, the efficient antibacterial properties have been validated in animal models bearing infections including wounds, pneumonia, caries, and bacterial vaginosis, demonstrating great translational potential. Lastly, we will s...

Biogenic FeS nanoparticles modulate the extracellular electron transfer and schwertmannite transformation

“…FeS NPs have the ability to maintain and promote microbial species metabolism to mediate EET; 9 however, some studies have reported that FeS can inhibit the growth of organisms, including microorganisms, 17,42 plants, 43 and zebrafish. 44 For instance, Cui et al 17 demonstrated that a long-term operation (46 d) in microbial fuel cells led to excess iron sulfide nanoparticles accumulating on the outer layer cells, which might negatively affect the microbial metabolisms.…”

“…Similarly, according to the trend of Fe 2+ production and the aggregation of iron-sulfur minerals on the cell surface, adjustments of the FeS synthesis rate and yield were also achieved by altering the initial S 2 O 3 2− precursor via self-regulation by S. oneidensis MR-1, while increasing the precursor concentration did not increase FeS biosynthesis, probably because excessive FeS was detrimental to S. oneidensis MR-1 metabolism. FeS NPs have the ability to maintain and promote microbial species metabolism to mediate EET; 9 however, some studies have reported that FeS can inhibit the growth of organisms, including microorganisms, 17,42 plants, 43 and zebrafish. 44 For instance, Cui et al 17 demonstrated that a long-term operation (46 d) in microbial fuel cells led to excess iron sulfide nanoparticles accumulating on the outer layer cells, which might negatively affect the microbial metabolisms.…”

Inorganic Fe-O and Fe-S oxidoreductases: paradigms for prebiotic chemistry and the evolution of enzymatic activity in biology

“…In addition, a nano-colloidal pyrite compound (“pyrite nanozyme”) has recently been shown to have a 3300-fold higher affinity for H 2 O 2 than Mag, with a more than 4000-fold higher catalytic activity ( Meng et al, 2021 ). It has also been shown that iron polysulfide particles possess POD, CAT and intrinsic glutathione oxidase (GSH-OXD)-like activity ( Xu et al, 2018 ; Cao et al, 2023 ). These iron sulfide colloids can decompose H 2 O 2 into free radicals and O 2 , promoting the release of polysulfides.…”

Research Progress in Iron-Based Nanozymes: Catalytic Mechanisms, Classification, and Biomedical Applications

“…Cao et al designed and synthesized a series of metastable iron sulfides, such as Fe 3 S 4 , Fe 1−x S, Fe 7 S 8 , and FeS. 108 They found that metastable iron sulfide has a multimode antibacterial mechanism, which can not only effectively kill a variety of Gram-positive and Gram-negative drug-resistant mutants but also eliminate bacteria in biofilms and cells. This mechanism is different from the traditional antibiotic bactericidal mechanism and therefore may provide a new antibacterial material for the resistance crisis.…”

“…Their experiment results showed that the PdFe/GDY nanozyme could consume GSH for bacterial disinfection with >99.99% killing effect, promote wound healing without significant toxicity both in vivo and in vitro, and can also be used as an effective antimicrobial agent for wound disinfection. Cao et al designed and synthesized a series of metastable iron sulfides, such as Fe 3 S 4 , Fe 1– x S, Fe 7 S 8 , and FeS . They found that metastable iron sulfide has a multimode antibacterial mechanism, which can not only effectively kill a variety of Gram-positive and Gram-negative drug-resistant mutants but also eliminate bacteria in biofilms and cells.…”