A Sulfonamide Intermediate Elicits Therapeutic Effect Against Sepsis by Enhancing Neutrophil Maturation

Abstract

Sepsis, a life-threatening condition characterized by systemic inflammation and immune dysregulation, remains a major cause of mortality worldwide. Here, we identify a synthetic sulfonamide intermediate, 1-[5-(2-fluorophenyl)furan-2-yl]-N-(4-methylbenzyl)methanamine (FMM), as a host-directed therapeutic candidate that enhances neutrophil maturation and antimicrobial function via autophagy. In a Pseudomonas aeruginosa-induced sepsis model, FMM administration markedly improved survival and attenuated inflammatory cytokine levels while reducing tissue injury and immune cell apoptosis. Furthermore, FMM promoted bone marrow neutrophil maturation, increased reactive oxygen species generation, and enhanced neutrophil extracellular trap formation. FMM also activated GPCR-mediated G beta gamma-PLC signalling, which triggered intracellular calcium and ERK/p38 phosphorylation. Notably, FMM lacked direct bactericidal activity, suggesting its therapeutic effects are mediated by host immune modulation rather than pathogen targeting. Collectively, these findings demonstrate that FMM exerts potent pharmacological effects on neutrophil function and represents a promising lead compound for developing host-directed immunomodulatory therapies for sepsis.