Garlic and Its Bioactive Derivatives as Host-Directed Therapies in Sepsis

Abstract: Sepsis, a life-threatening dysregulated host response to infection, urgently requires novel adjunctive therapies due to the limitations of antibiotics and rising multidrug resistance. Garlic and its bioactive organosulfur compounds, such as allicin and diallyl sulfides, demonstrate significant therapeutic potential for sepsis management through diverse mechanisms. Their efficacy primarily stems from simultaneous immunomodulation and antioxidant activity. Garlic derivatives suppress the NF-κB pathway to curtail excessive pro-inflammatory cytokine release and activate the Nrf2/HO-1 pathway to mitigate oxidative stress. Emerging research highlights that they help mitigate mitochondrial dysfunction by enhancing the PINK1/Parkin- mediated mitophagy pathway, thereby preserving cellular integrity. Beyond these host-directed effects, they exert direct, broad-spectrum antimicrobial activity against critical pathogens, including Pseudomonas aeruginosa, Escherichia coli , and Plasmodium species. Notably, they act synergistically with antibiotics and are effective against multidrug-resistant (MDR) strains. The pleiotropic actions of garlic compounds also confer protection against sepsis-induced multi-organ injury in major organs such as the lung, kidney, and liver. This combination of direct antimicrobial effects, immunomodulation, and organ protection positions garlic derivatives as a promising integrative therapeutic strategy. Given this broad therapeutic potential, further efforts will be required to translate these pleiotropic benefits into clinical practice and establish their efficacy through rigorous clinical trials for sepsis adjunctive therapy ultimately. Notably, current evidence predominantly relies on preclinical data, while critical clinical insights, such as the pharmacokinetics of allicin in humans, remain lacking, posing potential translational challenges. Keywords: sepsis, garlic, nuclear factor kappa B, NF-κB, diallyl disulfide, DADS, S-allyl cysteine, SAC