Serious infections by multi- or pan-resistant bacteria are causing more and more increasing concern in clinical microbiology, hospital hygiene and antibiotic management. Antibiotic resistance does therefore not only develop in hospitals and the community, but arises in parallel from excessive prophylactic antibiotic treatments in livestock farming. Uncontrollable spread in the environment and horizontal gene-transfer by bacteria multiplies this challenge frighteningly. In contrast, the pharmaceutical pipeline is almost empty with colistin being the last approved antibiotic that often represents the final treatment option of infections caused by multi-resistant Gram-negative Klebsiella pneumoniae and Pseudomonas aeruginosa pathogens.
In the last 20 years research focused on natural antimicrobial peptides (AMP) to investigate their clinical potential as a novel class of antibiotic drugs. Among the different AMP families proline-rich peptides like apidaecins and oncocins appear especially interesting as they act intracellularly on specific bacterial targets, e.g. heat shock protein DnaK. This class of AMPs does not penetrate eukaryotic membranes and does therefore not exhibit cytotoxic potential, as confirmed in vitro against eukaryotic cell lines and by hemolysis assays.
The optimized apidaecin derivatives Api88 and Api137 and oncocin derivatives Onc72 and Onc112 show minimal inhibitory concentrations in the low micromolar range and half life times of more than six hours in serum. Tolerance testing with NMRI mice treated four times intraperitoneally with a total daily dose of at least 160 mg/kg body weight revealed no adverse effects.
The in vivo antibacterial activity was examined using three different systemic intraperitoneal infection models with Escherichia coli and Klebsiella pneumoniae. When dosed intraperitoneally three times, the mean ED50 was around 1.25-2.5 mg/kg body weight. Pharmacokinetics in mice was investigated after single intraperitoneal and intravenous injections by a quantitative LC-MS/MS method from plasma, kidney and liver, linking the determined levels of the peptides to their therapeutic effect.