The antibacterial effect of a proline-rich antibacterial peptide A3-APO

• Published in: Current medicinal chemistry Vol. 16; no. 30; p. 3996
• Main Authors: Rozgonyi, F, Szabo, D, Kocsis, B, Ostorházi, E, Abbadessa, G, Cassone, M, Wade, J D, Otvos, Jr, L
• Format: Journal Article
• Language: English
• Published: United Arab Emirates 01-10-2009
• Subjects: Amino Acid Sequence; Animals; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Drug Design; Microbial Sensitivity Tests; Models, Molecular; Molecular Sequence Data; Peptides - chemistry; Peptides - pharmacology; Proline - chemistry; Proline - pharmacology
• ISSN: 1875-533X
• DOI: 10.2174/092986709789352295

Antimicrobial resistance is an emerging worldwide concern in light of the widespread antimicrobial drug use in humans, livestock and companion animals. The treatment of life-threatening infections is especially problematic because clinical strains rapidly acquire multiple-drug resistance. Antimicrobial peptides have long been considered to be viable alternatives to small molecule antibiotics. However, the peptides' parenteral use is frequently hampered by inadequate safety margins and rapid renal clearance leaving them suitable only for topical applications. The proline-rich peptide A3-APO represents a family of a new class of synthetic dimers that kill bacteria by a dual mode of action and carry domains for interaction with both the bacterial membrane and an intracellular target. From a series of designer antibacterial peptides, A3-APO emerged as a viable preclinical candidate by virtue of its superior ability to disintegrate the bacterial membrane, inhibit the 70-kDa heat shock protein DnaK alone or in synergy with small molecule antibiotics, lack of eukaryotic toxicity and withstand proteolytic degradation in body fluids. As many other proline-rich peptides, A3-APO binds to the C-terminal helical lid of bacterial DnaK and inhibits chaperone-assisted protein folding in bacteria but not in mammalian Hsp70. In this review, the structure, pharmacokinetic properties, antimicrobial spectrum of peptide A3-APO and its in vivo metabolite are summarized and the in vitro and in vivo antimicrobial effects (antimicrobial susceptibilities, postantibiotic effects, resistance induction) are discussed in detail.