The CDC has identified a number of bacteria as potential biowarfare agents. A current strategy to control infections following a bioterroristic attack is through the use of antimicrobial agents for both prophylactic and therapeutic purposes. The most significant challenge to this strategy is the presence of naturally-occurring drug resistance and the demonstrated ease of engineering drug-resistance in many biowarfare strains. Therefore, there is a strong need for the development of new antibacterial agents that can evade molecular mechanisms and host responses associated with the development drug resistant strains. PolyMedix is presently developing a series of nonpeptidic compounds that are uniquely suited for therapeutic and material applications against biowarfare organisms. These biomimetic compounds mimic key biological properties of proteins, and are more stable and inexpensive to produce than natural proteins. The first application of this technology has been the design and synthesis of non-peptidic mimetics of host defense peptides that play a critical role in health, serving as a first line of attack against a wide range of microbes. In relation to their naturally occurring counterparts, the mimetics are significantly smaller and easier to prepare, as equipotent and as broadly active. However, the non-peptidic mimetics are significantly less toxic towards human erythrocytes, much less expensive to prepare, and should be much more stable. Furthermore, the compounds retain their antimicrobial activity in polymeric forms, and when applied to solid surfaces or incorporated into a plastic such as polyurethane. Importantly, because these compounds mimic the structure and biological activity of host defense peptides, the appearance of bacterial resistant strains is very unlikely to occur. Presently, eight classes of mimetics, distinguished by the chemical composition of their molecular backbone, have been synthesized and tested for antimicrobial activity. The goal of the Phase I studies is to identify compounds that 1) kill a broad spectrum of biowarfare agents and are not cytotoxic for mammalian cells 2) display mechanistic properties important for antimicrobial applications against biowarfare pathogens; rapid bactericidal activity and low incidence for the development of bacterial resistance. These studies will provide critical proof-of-concept information on the antimicrobial activities of the current compound series against the biowarfare organisms. In Phase II, thorough lead optimization will be done on the first generation lead compounds for subsequent development of specific therapeutic and material applications. ? ?
| Dawson, Michael John; Scott, Richard W (2012) New horizons for host defense peptides and lantibiotics. Curr Opin Pharmacol 12:545-50 |
