Targeting Alpha-Toxin: Exploring Flavonoid-Based Strategies Against Clostridium perfringens Reservoirs in Insects

Abstract

Insects that thrive in decaying organic matter often act as hidden reservoirs of Clostridium perfringens, carrying the bacterium within their gut microbiota and amplifying its presence in the environment. This ecological relationship enables the dissemination of C. perfringens, particularly its biotype A strains, which produce phospholipase C (Cp-PLC), also known as alpha-toxin. Alpha-toxin is a key virulence factor, disrupting critical signaling pathways in endothelial cells, platelets, and neutrophils. This disruption triggers an overproduction of intercellular mediators and adhesion molecules, leading to severe tissue damage and gas gangrene—a life-threatening condition characterized by necrosis and gas production in infected tissues. While most C. perfringens infections are self-limiting, current treatment strategies primarily offer symptomatic relief without targeting the underlying bacterial presence. This highlights the urgent need for innovative therapeutic interventions to combat severe C. perfringens-related conditions. Our research explores the potential of phytochemical flavonoids, natural compounds with proven antioxidant, antibacterial, anti-inflammatory, and immune-modulating properties, as alternative therapeutic agents. By disrupting gut microbial communities in insect hosts using flavonoids or antibacterial compounds, we propose an indirect pest management approach that reduces the spread of C. perfringens. We evaluated the binding interactions and affinities of 15 flavonoids against alpha-toxin using molecular docking techniques. These flavonoids were selected based on their bioactive properties and compliance with Lipinski’s Rule of Five. Among the tested compounds, hesperidin, boldione, curcumin, and protopine demonstrated strong binding affinities to the catalytic domain of alpha-toxin, with binding energies of -12.4, -12.0, -9.0, and -8.7 kcal/mol, respectively. Notably, with well-documented antibacterial properties, curcumin, and hesperidin showed promise in inhibiting C. perfringens proliferation within insect hosts, reducing their role as bacterial vectors while impairing insect physiology. Future research will focus on validating these findings to assess their practical applications across medical, agricultural, and ecological domains.