By Richard W. Scott
FEATURE
Defensin
Mimetics: Using Nature To Keep Us Safer Despite enormous advances in the evolution of anti-infective treatments, most authorities think we are losing the battle against microorganisms. Resistance to antimicrobial agents has developed in every notable strain of pathogenic bacteria, and to basically every commercially available antibiotic. The advent of such “superbugs” is one of the most crucial medical dilemmas the world is currently facing. Over 2.5 million residents of the US suffer acute bacterial infections annually, and over 100,000 of these individuals lose their lives, making infections the fourth-highest cause of mortality in the country and the second leading cause of death across the globe. Those who live put up with longer stays in hospital and need to be treated with costly second- and third-line antibiotics that often produce harmful side-effects. The global market for anti-infective medications, estimated at more than $45 billion annually, is growing due to the increase in bacterial drug resistance. For example, the number of hospitalizations in the US between 1999 and 2005 associated with MRSA infections grew 119 per cent. The most striking rise (approximately 400 per cent) during this period was identified with infections that characteristically occur outside rather than inside hospitals. Previously, MRSA frequently affected hospitalized surgical patients or individuals with compromised immune systems. Recently, it has manifested itself as a community-based infection in otherwise healthy people. Two years ago, about 686,000 hospitalizations for MRSA infections occurred in the US, which resulted in direct healthcare expenses of almost $10 billion and a total bill of approximately $118 billion. The very real prospect of our antibiotic defenses losing their effectiveness or becoming obsolete has produced an urgent need for antimicrobial agents that work via mechanisms that bacteria have not yet recognized.
Ancient defense mechanisms The path to concocting the antibiotics of the future may involve ancient defense molecules. Molds and other primitive organisms rely on biochemically acting agents to protect against bacteria. Penicillin, created for this purpose by molds, is perhaps the most well-known example. Mammals have a more sophisticated defense against bacteria, the first line of which comprises the host defense peptides (HDPs), known as defensins in humans. These molecules, which make up part of the nonhumoral or innate immune response, quickly eradicate bacteria before the pathogens can dominate. Biologists have found numerous types of HDPs. Although they and human defensins both have a varied array of amino acid sequences, they have similar physicochemical characteristics. All are amphiphilic, meaning they have an affinity for both charged/polar and uncharged/ nonpolar environments. It is this characteristic, rather than amino acid sequence, that lies behind HDPs’ antimicrobial activity, which has remained robust in spite of hundreds of millions of years of bacterial evolution. 12 BIOTECHNOLOGY FOCUS APRIL 2010
