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Title: Antimycobacterial activity of bacteriocins and their complexes with liposomes

Author
item SOSUNOV, VASILY - LAB FOR IMMUNO RUSSIA
item MISCHENKO, VLADIMIR - LAB FOR IMMUNO RUSSIA
item ERUSLANOV, BORIS - ST RES CTR RUSSIA
item SVETOCH, EDWARD - ST RES CTR RUSSIA
item SHAKINA, YULIA - ST RES CTR RUSSIA
item Stern, Norman
item MAJOROV, KONSTANTIN - LAB FOR IMMUNO RUSSIA
item SOROKOUMOVA, GALINA - ST AC OF FINE CHEM RUSSIA
item SELISHCHEVA, ALLA - MOSCOW ST UNIV
item APT, ALEXANDER - LAB FOR IMMUNO RUSSIA

Submitted to: Antimicrobial Chemotherapy
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/1/2007
Publication Date: 3/8/2007
Citation: Sosunov, V., Mischenko, V., Eruslanov, B., Svetoch, E., Shakina, Y., Stern, N.J., Majorov, K., Sorokoumova, G., Selishcheva, A., Apt, A. 2007. Antimycobacterial activity of bacteriocins and their complexes with liposomes. Antimicrobial Chemotherapy. Vol 59. pg 919-925.

Interpretive Summary: Bacteriocins (Bcn) are natural proteins produced by various bacteria which kill other bacterial species. Mycobacterium tuberculosis is the deadly pathogen that is responsible for causing TB in humans, with a yearly worldwide death toll of >2-3 million people per year. We studied 5 Bcn for potential application to control TB. In laboratory studies, four of five Bcn killed TB at levels which were superior to the most commonly used antibiotic, rifampicin. However, when the TB cells were sequestered within mouse macrophage (as is the case in infections), Bcn treatment failed to penetrate and kill the TB bacterium. We then created an oil-in-water system (liposome) containing the Bcn to “fool” the macrophage to eat this Bcn system and kill the TB cells. When this Bcn-liposome Trojan-horse system was fed to TB infected mice, the animals survived significantly longer than did the non-treated control mice. There has been a recent worldwide rise in antibiotic resistance among TB and alternative treatments are required. As our Bcn Trojan-horse system provides a totally different means of killing TB our approach merits further study.

Technical Abstract: Bacteriocins (Bcn) are natural peptides that are secreted by taxonomically distinct bacteria which exert bactericidal activity against other bacterial species. Their capacity to inhibit growth of virulent Mycobacterium tuberculosis H37Rv was evaluated in this study. Five Bcn were purified from select bacterial supernatants and activity against mycobacteria was assessed by three methods. In vitro mycobacterial cultures, in vitro infection of mouse macrophages and in vivo high-dose infection of inbred mice. In the in vitro model, four of five Bcn exhibited stronger antimycobacterial activity than equal concentrations of a widely used anti-TB antibiotic, rifampicin. These Bcn were non-toxic for mouse macrophages at a concentration 0.1 mg/L. Pure Bcn did not inhibit mycobacterial growth within murine macrophages when added at 0.01 to 0.1 mg/L, suggesting that at physiologically tolerable concentrations Bcn do not penetrate through the macrophage cells. However, when administered as a complex with phophatidylcholine-cardiolipin liposomes, Bcn5 demonstrated capacity both to inhibit intracellular growth of M. tuberculosis and to prolong survival of mice in an acute TB model. Because Bcn mechanism of bactericidal activity differs from that of all commonly used antibiotics, their possible involvement in complex TB therapies deserves further study.