A Tachyplesin Antimicrobial Peptide from Theraphosidae Spiders with Potent Antifungal Activity Against Cryptococcus neoformans

The venoms of Theraphosidae spiders have evolved into diverse natural pharmacopeias through selective pressures. <i>Cryptococcus neoformans</i> is a global health threat that frequently causes life-threatening meningitis and fungemia, particularly in immunocompromised patients. In this study, we identify a novel anti-<i>C. neoformans</i> peptide, QS18 (QCFKVCFRKRCFTKCSRS), from the venom gland of China's native spider species <i>Chilobrachys liboensis</i> by utilizing bioinformatic tools. QS18 shares over 50% sequence similarity with tachyplesin peptides, previously identified only in horseshoe crab hemocytes, expanding the known repertoire of the tachyplesin family to terrestrial arachnids. The oxidative folding of QS18 notably enhances its antifungal activity and stability, resulting in a minimum inhibitory concentration of 1.4 µM. The antimicrobial mechanism of QS18 involves cell membrane disruption. QS18 exhibits less than 5% hemolysis in human erythrocytes, indicating microbial selectivity and a favorable safety profile for therapeutic use. Furthermore, mouse model studies highlight QS18's ability as an antifungal agent with notable anti-inflammatory activity. Our study demonstrates QS18 as both a promising template for spider venom peptide research and a novel candidate for the development of peptide antifungals.