Recently, researchers 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 its derivatives have potential as new antimicrobials. Structural information obtained to date indicates that Tagetitoxin is much different than the known antibiotics that are RNA polymerase inhibitors.The goals of Phase I research are:(1) to investigate media and fermentation parameters that will allow efficient and consistent growth of the toxinproducing bacterium, along with production of reproducibly high levels of Tagetitoxin;(2) to scale up and improve puriEcation methods; and(3) to determine the exact structure of Tagetitoxin by using instrumental, chemical, and enzymatic methods.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.Awardee's statement of the potential commercial applications of the research:Since their discovery, antibiotics and other antimicrobials have had a profound impact on human health, with a concomitant financial gain for their inventors and manufacturers. The worldwide market for antimicrobials in 1985 was at least $16 billion. To increase the range and keep ahead of resistance, new compounds with new modes of action are continually sought. Tagetitoxin may be such a compound.National Institute of Allergy and Infectious Diseases (NIAID)
