The molecular mechanism by which novel antibacterial peptides inhibit Cryptococcus neoformans

Background Cryptococcosis, caused by Cryptococcus neoformans , is a major global public health concern. The infection primarily begins in the lungs. Cryptococcosis is characterized by significant consequences and low cure rates in immunocompromised individuals. Pulmonary cryptococcosis has become more common in recent years. Amphotericin B (AmB) and fluconazole (FLC) are commonly used as first-line medications in clinical treatment. However, the increasing incidence of azole resistance has led to an increase in clinical treatment failure rates. Antimicrobial peptides (AMPs) are considered attractive substitutes for conventional antibiotics for resolving this urgent problem because of their distinct processes and low risk of resistance development. Our earlier research revealed antimicrobial peptide-17 (AMP-17), which has a molecular weight of 17 kDa, as a possible antifungal agent from the transcriptome database of Musca domestica generated by Candida albicans . Nevertheless, the use of quantitative structure-activity relationship (QSAR) techniques to modify AMP-17 has not been used to investigate the antifungal mechanisms of AMP-17 derivatives. Results This study examined the potential potency of the peptide AMP-17-6 against clinically drug-resistant C. neoformans 314. The results revealed that AMP-17-6 possesses high bacteriostatic activity and bactericidal efficiency against C. neoformans 314, with a minimum inhibitory concentration (MIC) of 4 μg/mL. Additionally, AMP-17-6 is sensitive to trypsin and pepsin but is stable in a range of serum conditions and temperatures. Mechanistic studies revealed that AMP-17-6 induces membrane damage by targeting fungal-specific membrane components and dissipating the proton motive force (PMF), leading to metabolic disturbances and the accumulation of toxic metabolic byproducts. In a mouse model of pneumonia induced by C. neoformans 314 infection, AMP reduced the fungal burden and inflammatory reactivity in lung tissue. Conclusion These data demonstrate that AMP exhibits significant antibacterial efficacy against C. neoformans 314 by decreasing fungal viability and displaying antivirulence effects, suggesting its potential as a novel antibacterial drug for the treatment of resistant C. neoformans infections.