Bacterial growth blocked by a synthetic peptide based on the structure of a human proteinase inhibitor

Abstract

Cysteine proteinases are important not only in the intracellular catabolism of peptides and proteins¹ and in the processing of prohormones and proenzymes^2,3, but also in the penetration of normal human tissue by malignant cells4 and possibly microorganisms⁵, including viruses. Cystatin C is a human cysteine proteinase inhibitor present in extracellular fluids⁶. We have synthesized peptide derivatives mimicking the proposed proteinase-binding centre of cystatin C⁷ and find that they irreversibly inhibit cysteine proteinases. Several bacteria produce proteinases, so we tested a tripeptide derivative (Z-LVG-CHN₂) for in vitro anti-bacterial activity against a large number of bacterial strains belonging to thirteen different species. It was found to inhibit specifically the growth of all strains of group A streptococci. The susceptibility of these human pathogens to the peptide was compared with that to well-established anti-streptococcal antibiotics such as tetracy-cline and bacitracin. Moreover, the peptide was active in vivo against group A streptococci: mice injected with lethal doses of these bacteria were cured by a single injection of Z-LVG-CHN₂. The cysteine proteinase produced by group A streptococci was isolated and found to be inhibited by Z-LVG-CHN₂; moreover, excess proteinase relieved the growth inhibition caused by the peptide derivative, suggesting that the antibacterial activity of Z-LVG-CHN₂ is due to inhibition of this cysteine proteinase. This strategy of blocking proteinases with peptide derivatives that mimic naturally occurring inhibitors could be useful in the construction of new agents against other microorganisms, including viruses.