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

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 summarize the challenges of iron sulfides, proposing a possible development direction in the future. Our studies on iron sulfides can serve as a paradigm for the design and discovery of antibacterial nanomaterials, which may contribute for the war against drug-resistant pathogenic bacteria.