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

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• 作者：Patricia Czihal ; Daniel Knappe ; Stefanie Fritsche ; Michael Zahn ; Nicole Berthold ; Stefania Piantavigna ; Uwe M眉ller ; Sylvia Van Dorpe ; Nicole Herth ; Annegret Binas ; Gabriele K枚hler ; Bart De Spiegeleer ; Lisandra L. Martin ; Oliver Nolte ; Norbert Str盲ter ; Gottfried Alber ; Ralf Hoffmann
• 刊名：ACS Chemical Biology
• 出版年：2012
• 出版时间：July 20, 2012
• 年：2012
• 卷：7
• 期：7
• 页码：1281-1291
• 全文大小：596K
• 年卷期：v.7,no.7(July 20, 2012)
• ISSN：1554-8937

文摘

The 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 尾-lactamase (ESBL) or the novel New Delhi metallo-尾-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 K_D of 5 渭mol/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.