Natural antibacterial oligopeptides have been dis- covered in practically all living organisms. Whereas in prokaryotes these oligopeptides regulate competition between separate species occupying ecological niches and function as the signaling molecules in processes of inter- cellular communication [1], in eukaryotes they are local- ized in every organ and tissue and play a key role in innate immunity [2]. The functional class of antimicrobial oligopeptides involves structures, which display an unusually broad spectrum of antibacterial, antifungal, antiviral, and anti- tumor activities. These peptides are able to suppress or kill not only Gram-negative and Gram-positive bacteria, but also fungi, parasites, cancer cells, as well as HIV virus and herpes simplex virus. Antimicrobial oligopeptides that are known today, produced in response to infection or injury, are quite selective for microbes over eukaryotic cells. In animals, antimicrobial peptides are found in dif- ferent body parts and organs most likely to come into contact with pathogenic microbes. They have been detected in the skin, ears, and eyes, on epithelial surfaces of the tongue, tracheas, lungs, and gut, and in the bone marrow and testes; in blood they are most prevalent in neutrophils [3]. Interest in antimicrobial, especially antibacterial oligopeptides is determined by their medicinal potential. This is particularly important because of the continuous emergence of novel strains of bacteria that are resistant to natural and synthetic antibiotics, which prompts the search for new efficacious remedies against pathogenic bacteria. The functional properties of antibacterial oligopeptides are realized in different ways depending on the peculiarity of their structure. These peptides are char- acterized by compact, completely or partially helical structures formed with cysteine bridges as well as by dis- ordered structures. An important role in formation of dis- ordered oligopeptide structures belongs to proline residues, which constitute a large part of the total number of amino acid residues in relatively short oligopeptide molecules. Because of a significant number of proline- rich natural antibacterial oligopeptides, a question arises as to how unique is the mechanism of action of these pep- tides. This review systematizes the data on structure and functions of some structural-homologous members of families of proline-rich oligopeptides (PRO) possessing antibacterial activity, and it contains a discussion of the mechanism of their action. OLIGOPEPTIDES WITH HIGHER CONTENT OF PARTICULAR AMINO ACID RESIDUES The ANTIMIC database [4] contains information on ~1700 natural antimicrobial peptides that differ in their chemical structures and functions. The EROP- Biochemistry (Moscow), Vol. 69, No. 10, 2004, pp. 1082-1091. Translated from Biokhimiya, Vol. 69, No. 10, 2004, pp. 1332-1344. Original Russian Text Copyright © 2004 by Markossian, Zamyatnin, Kurganov. REVIEW 0006-2979/04/6910-1082 ©2004 MAIK “Nauka / Interperiodica” * To whom correspondence should be addressed. Antibacterial Proline-Rich Oligopeptides and Their Target Proteins K. A. Markossian*, A. A. Zamyatnin, and B. I. Kurganov Bach Institute of Biochemistry, Russian Academy of Sciences, Leninsky pr. 33, Moscow 119071, Russia; fax: (7-095) 954-2732; E-mail: markossian@inbi.ras.ru Received February 2, 2004 Revision received April 28, 2004 Abstract—This review presents findings on a new family of antibacterial proline-rich oligopeptides—pyrrhocoricin, drosocin, apidaecin, and formaecin—isolated from insects. The functional and physicochemical properties of proline-rich oligopep- tides are considered, a role of proline in their antibacterial activity is discussed, and experimental evidence is given in favor of the ability of these oligopeptides to suppress metabolism of bacteria by means of stereospecific interaction with heat shock protein DnaK and inhibition of DnaK-dependent protein folding. Binding of the peptides under investigation with DnaK correlates with their antibacterial activity. Evidence that pyrrhocoricin, drosocin, apidaecin, and formaecin are nontoxic for human and animal cells serves as a prerequisite for their use as novel antibiotic drugs. Key words: proline-rich oligopeptides, heat shock proteins, folding, antibacterial activity, EROP-Moscow database