Engineered killer mimotopes: new synthetic peptides for antimicrobial therapy.
This review deals with a novel approach to produce synthetic antibiotic peptides (killer mimotopes), similar to those described for the conversion of epitopes into peptide mimotopes, allowing their use as surrogate vaccines. Synthetic peptides pertaining to the complementary determining regions (CDRs) of a recombinant antiidiotypic antibody (PaKTscFv), which mimic the wide spectrum of microbicidal activity of a killer toxin produced by the yeast Pichia anomala (PaKT), have proven to act as structural or functional mimotopes of PaKT. This activity appeared to be mediated by interaction with specific cell wall killer toxin receptors (KTRs), mainly constituted by beta glucans. Killer mimotopes have shown in vitro an impressive microbicidal activity against Candida albicans. They were adopted as a model of PaKT- and PaKTscFv-susceptible microorganisms. Optimization through alanine scanning led to the generation of an engineered decapeptide (KP) of a CDR-L1 pertaining antibody fragment with an enhanced in vitro microbicidal activity. It had a potent therapeutic effect against experimental vaginal and systemic candidiasis in normal and immunodeficient mice caused by flucanozole susceptible and resistant yeast isolates. KP exerted a microbicidal activity in vitro against multidrug-resistant eukaryotic and prokaryotic pathogenic microorganisms, which was neutralized by interaction with laminarin (beta 1,3-glucan). To our knowledge, KP represents the prototype of an engineered peptide fragment derived from a microbicidal recombinant antiidiotypic antibody. It is capable of exerting antimicrobial activity in vitro and a therapeutic effect in vivo presumably acting through interaction with the beta glucan KTR component in the cell walls of pathogenic microorganisms.
Sezione di Microbiologia, Dipartimento di Patologia e Medicina di Laboratorio, Università degli Studi di Parma, Viale Antonio Gramsci 14, 43100 Parma, Italy. magliwal@unipr.it
W
W
Magliani
S
S
Conti
A
A
Salati
S
S
Arseni
L
L
Ravanetti
R
R
Frazzi
L
L
Polonelli
D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000888:Antibodies, Anti-Idiotypic / Q000627:therapeutic use; D005818:Genetic Engineering; D055646:Killer Factors, Yeast; D051379:Mice; D009183:Mycotoxins / Q000494:pharmacology; D010455:Peptides / Q000235:genetics / Q000627:therapeutic use*; D015202:Protein Engineering; D014614:Vaccines, Synthetic / Q000494:pharmacology / Q000627:therapeutic use
D000890:Anti-Infective Agents; D000888:Antibodies, Anti-Idiotypic; D055646:Killer Factors, Yeast; D009183:Mycotoxins; D010455:Peptides; D014614:Vaccines, Synthetic