A synthetic peptide as a novel anticryptococcal agent.
An engineered, killer decapeptide (KP) has been synthesized based on the sequence of a recombinant, single-chain anti-idiotypic antibody (KT-scFv) acting as a functional internal image of a yeast killer toxin. Killer decapeptide exerted a strong fungicidal activity against Candida albicans, which was attributed to peptide interaction with beta-glucan. As this polysaccharide is also a critical component of the cryptococcal cell wall, we wondered whether KP was also active against Cryptococcus neoformans, a human pathogen of increasing medical importance. We found that KP was able to kill both capsular and acapsular C. neoformans cells in vitro. Furthermore, KP impaired the production of specific C. neoformans virulence factors including protease and urease activity and capsule formation, rendering the fungus more susceptible to natural effector cells. In vivo treatment with KP significantly reduced fungal burden in mice with cryptococcosis and, importantly, protected the majority of immunosuppressed animals from an otherwise lethal infection. Given the relevance of cryptococcosis in immunocompromised individuals and the inability of conventional drugs to completely resolve the infection, the results of the present study indicate KP as an ideal candidate for further studies on novel anticryptococcal agents.
Cenci
Elio
E
Microbiology Section, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy.
Bistoni
Francesco
F
Mencacci
Antonella
A
Perito
Stefano
S
Magliani
Walter
W
Conti
Stefania
S
Polonelli
Luciano
L
Vecchiarelli
Anna
A
D000818:Animals; D000935:Antifungal Agents / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D002176:Candida albicans / Q000187:drug effects; D003453:Cryptococcosis / Q000188:drug therapy; D003455:Cryptococcus neoformans / Q000187:drug effects* / Q000378:metabolism / Q000472:pathogenicity; D004305:Dose-Response Relationship, Drug; D005260:Female; D005936:Glucans; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000378:metabolism / Q000382:microbiology; D008543:Melanins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism / Q000382:microbiology; D010455:Peptides / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D011134:Polysaccharides / Q000378:metabolism; D015996:Survival Rate; D037521:Virulence Factors / Q000378:metabolism; D047071:beta-Glucans / Q000378:metabolism
D000935:Antifungal Agents; D005936:Glucans; D008543:Melanins; D010455:Peptides; D011134:Polysaccharides; D037521:Virulence Factors; D047071:beta-Glucans; C002076:pustulan; C008247:laminaran