We have tried to approach the problem of creating an effective microbicide by exploiting the powerful antimicrobial substances utilized by animals in their effective defense against microbes (1,2,3). In one scenario, the antimicrobial peptide is used as a 'shield' applied to the vaginal cavity. In a second scenario, a very inexpensive, safe substance, capable of stimulating expression of higher levels of protective antimicrobial agents in the vaginal cavity is locally applied. All animals, including man, express broad-spectrum antimicrobial peptides from epithelial surfaces exposed to microbes (2,3). These peptides, which include molecules such as defensins and magainins, exhibit a broad spectrum of action including almost all STD pathogens (viruses included), are bactericidal, rapidly acting. In addition, normal commensual bacteria, such as Lactobacilli are relatively resistant to the action of these endogenous antimicrobial agents. SCENARIO #1: Thousands of analogues of antimicrobial peptides have been synthesized (4). Pexiganan, a synthetic analogue of magainin, is the first of this class to be developed as a therapeutic and has proved itself to be safe and effective in the topical treatment of infected ulcers in diabetics in over 1000 people in two Phase 3 clinical trials. Its spectrum against several thousand clinical bacterial isolates has been published, demonstrating as well, the low level of induction of resistance, lack of cross-resistance with other known antibiotics, and disinfectant-like kinetics of action (5). We propose that a gel containing a molecule of this type would have antimicrobial properties and potential long-term safety ideal for a topical microbicide. SCENARIO #2: We have discovered, in the course of a targeted search of inducers of human epithelial antimicrobial peptides, several safe, inexpensive substances that offer promise of a new approach to the protection of women from STD. The most interesting are two substances: the amino acid, isoleucine and heat killed probiotic bacteria, Lactobacilli. When introduced into a culture of epithelial cells expressing an inducible defensin gene, isoleucine potently stimulates transcription of the defensin gene. The mechanism by which it does this involves the NFkB pathway. Structure-activity studies reveal the importance of certain chiral centers of the isoleucine structure. We have discovered that when isoleucine is fed to certain animals the flora of the GI tract become dominated by Lactobacilli. We believe this to occur through the following mechanism. Isoleucine stimulates epithelial expression of defensins, reducing numbers of defensin-sensitive flora providing the more resistant lactobacilli with a growth advantage. The Lactobacilli, in turn, further stimulate defensin gene expression, stabilizing the bacterial ecology of the GI tract. We propose that a microbicide be created incorporating isoleucine into a gel, to be applied directly into the vagina. This preparation would be expected, by analogy to what we have observed in the GI tract, to enhance the proportion of Lactobacilli, an end-point that could be evaluated in initial clinical trials. An expected benefit of enhanced defensin expression, as well as stabilization of 'good bacteria,' should be reduced incidence of STD in the population, which could be evaluated in a second independent study. This approach solves problems involving cost of goods and safety on long-term use that complicates worldwide development of microbicides for the prevention of STDs.