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Title: SMALL, ANIONIC, AND CHARGE-NEUTRALIZING PROPEPTIDE FRAGMENTS OF ZYMOGENS ARE ANTIMICROBIAL

Author
item Brogden, Kim
item Ackermann, Mark
item HUTTNER, KENNETH M - BOSTON CHILDRENS HOSPITAL

Submitted to: Cell
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/24/1997
Publication Date: N/A
Citation: N/A

Interpretive Summary: Pneumonia is a major economic problem of the cattle industry in North America. Affected cattle often have severe lung damage and their lung tissues can contain large numbers of bacteria. Despite numerous commercial vaccines, shipping fever pneumonia still exists and causes estimated losses of 0.7 to 1 billion dollars annually to ranchers and producers. Mechanisms sof natural resistance are being examined as a way to reduce these losses. One mechanism involves small proteins we recently found in the lung fluid of sheep and cattle. These proteins act as natural antibiotics in the lungs. In this study, we made small protein antibiotics from lung fluid that killed the bacterium that causes shipping fever of cattle (and other bacteria). In mice as an experimental model of infectiion, pneumonia was reduced in severity after mice were given the small protein antibiotic. These proteins may form a new class of natural antibiotics and we believe will be important in defense against bacteria that cause pneumonia in animals. These antibiotics may be given to healthy animals to prevent disease or to sick animals after infection to treat pneumonia.

Technical Abstract: Some zymogens contain small amino terminus, homopolymeric regions of Asp that neutralize cationic proteins of divergent functions. After post-transcriptional modification, these cleaved anionic propeptides have antimicrobial activity. To demonstrate this, pulmonary surfactant-associated anionic peptide (SAAP), trypsinogen activation peptide, and the precursor sequence of the prohormone PYL from Xenopus laevis was synthesized and tested for antimicrobial activity in vitro and in vivo. All 3 peptides were bactericidal with zinc for 5 procaryotic organisms but not eucaryotic organisms (BL-3 lymphocytes and Candida krusei). Gram-negative bacteria were more susceptible (MBC50 range 0.05 - 0.64 mM) than Gram-positive bacteria (MBC50. range 0.76 - 1.81 mM). SAAP (4 mg i.v./Kg) significantly reduced Klebsiella pneumoniae pulmonary infection in mice. Anionic propeptides, distinct from larger cationic defensins, form a new class of antimicrobial peptides and may be important in innate defense against microbial infection.