cb300063v_si_001.pdf (685.89 kB)
Api88 Is a Novel Antibacterial Designer Peptide To Treat Systemic Infections with Multidrug-Resistant Gram-Negative Pathogens
journal contribution
posted on 2012-07-20, 00:00 authored by 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 HoffmannThe emergence of multiple-drug-resistant (MDR) bacterial
pathogens
in hospitals (nosocomial infections) presents a global threat of 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 the antibacterial peptide apidaecin
1b, we have optimized the sequence to treat systemic infections with
the most threatening human pathogens, such as Escherichia
coli, Klebsiella pneumoniae, Pseudomonas
aeruginosa, and Acinetobacter baumannii.
The lead compound Api88 enters bacteria without lytic effects at the
membrane and inhibits chaperone DnaK at the substrate binding domain
with a KD of 5 μmol/L. The Api88-DnaK
crystal structure revealed that Api88 binds with a seven residue long
sequence (PVYIPRP), in two different modes. Mice did not show any
sign of toxicity when Api88 was injected four times intraperitoneally
at a dose of 40 mg/kg body weight (BW) within 24 h, whereas three
injections of 1.25 mg/kg BW and 5 mg/kg BW were sufficient to rescue
all animals in lethal sepsis models using pathogenic E. coli strains ATCC 25922 and Neumann, respectively. Radioactive labeling
showed that Api88 enters all organs investigated including the brain
and is cleared through both the liver and kidneys at similar rates.
In conclusion, Api88 is a novel, highly promising, 18-residue peptide
lead compound with favorable in vitro and in vivo properties including a promising safety margin.