Api88 Is a Novel Antibacterial Designer Peptide To Treat Systemic Infections with Multidrug-Resistant Gram-Negative Pathogens

• DOI: 10.1021/cb300063v
• Publication Date: 2012-05-17T20:20:41Z
• Authors: Patricia Czihal; Daniel Knappe; Stefanie Fritsche; Michael Zahn; Nicole Berthold; Stefania Piantavigna; Uwe Müller; Sylvia Van Dorpe; Nicole Herth; Annegret Binas; Gabriele Köhler; Bart De Spiegeleer; Lisandra L. Martin; Oliver Nolte; Norbert Sträter; Gottfried Alber; Ralf Hoffmann
• Keywords: Gram; Gram-Negative Bacteria; Antibacterial peptide

The emergence of multiple-drug-resistant (MDR) bacterial pathogens in hospitals (nosocomial infections) presents a global threat growing importance, especially for Gram-negative bacteria with extended spectrum β-lactamase (ESBL) or the novel New Delhi metallo-β-lactamase 1 (NDM-1) resistance. Starting from antibacterial peptide apidaecin 1b, we have optimized sequence to treat systemic infections most threatening human pathogens, such as Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. lead compound Api88 enters without lytic effects at membrane inhibits chaperone DnaK substrate binding domain KD 5 μmol/L. Api88-DnaK crystal structure revealed that binds seven residue long (PVYIPRP), two different modes. Mice did not show any sign toxicity when was injected four times intraperitoneally dose 40 mg/kg body weight (BW) within 24 h, whereas three injections 1.25 BW were sufficient rescue all animals lethal sepsis models using pathogenic E. coli strains ATCC 25922 Neumann, respectively. Radioactive labeling showed organs investigated including brain is cleared through both liver kidneys similar rates. In conclusion, novel, highly promising, 18-residue favorable vitro vivo properties promising safety margin.