Recently, researchers at the University of Wisconsin-Madison found that the bacterial phytotoxin Tagetitoxin is a potent inhibitor of Escherichia coli RNA polymerase in vitro. This common mechanism of action with known antibiotics such as rifampicin and streptolydigin suggests that Tagetitoxin or derivatives thereof have potential as new antimicrobials. Structural information obtained to date indicates that Tagetitoxin is much different than the known antibiotics which are RNA polymerase inhibitors. Thus, the goals of Phase I research are: (1) to investigate media and fermentation parameters which will allow efficient and consistent growth of the toxin-- producing bacterium, along with production of reproducibly high levels of Tagetitoxin, (2) to scale up and improve purification methods, and (3) to determine the exact structure of Tagetitoxin by growing suitable crystals of the native toxin or its derivatives for X-ray crystallographic analysis. The structural knowledge obtained in Phase I will be used in Phase II to synthesize and evaluate new Tagetitoxin analogs for bacterial permeability, RNA polymerase inhibitory activity, antimicrobial activity, and structure/activity relationships, with the ultimate aim of developing Tagetitoxin or its derivatives into a new family of antimicrobial products for human and/or veterinary medicine.
