NOVEL ANTIMICROBIALS BASED ON ARYLHYDRAZONES

DESCRIPTION: (Adapted from the Applicant's Abstract). This proposal discusses the development of small molecule, orally active antimicrobial agents acting by modulation of bacterial transcription. Novel antibiotics disrupting transcription are likely to overcome important limitations of existing antibiotics because of reduced development of resistance. Although bacterial infections were considered well controlled, the threat posed by the emergence of multidrug-resistant organisms is now apparent. Transcription-targeted therapy offers new targets that are now addressed by existing antibiotics. Choosing transcription targets that represent multigene families will reduce the rate at which resistance emerges. Established high throughput in vitro assays at SCRIPTGEN have uncovered a class of molecules that inhibit bacterial transcription specifically. Medicinal chemistry for this program has begun and analogs of increased potency and specificity have been prepared. Secondary screens indicate that some analogs exhibit thousand fold specificity for inhibition of pathogenic bacterial RNA polymerases versus human RNA polymerase. The molecules are arylhydrazones whose structure and ease of analog preparation make them highly amenable to a medicinal chemistry program. Arylhydrazones possess structural features that make them less than optimal drug candidates. Structural modifications to increase potency, specificity, and bioavailability, while attenuating toxicity are proposed. $ = TOTAL AWARD AMTS & NOT LIMITED TO PORTION OF PROJECT RELATED TO SUBJECT OF SEARCH SUBPROJECT $ = TOTAL AWARD AMOUNT DIVIDED BY NUMBER OF SUBPROJECTS SOURCE: CRISP FORMAT F FY 97 LAST UPDATE 04-07-98 1QUERY 1536 ID SEARCH 06/01/98 PAGE 50 --PROJECT NUMBER......1 R43 AI39870-01A2 INVESTIGATOR NAME/ADDRESS FY 97 STINCHCOMBE, TIMOTHY J IRG/INTRAMURAL UNIT..ZRG2 TERA BIOTECHNOLOGY CORP AWARD AMOUNT......... $99,373 3099 SCIENCE PARK ROAD SAN DIEGO, CA 92121 PERFORMING ORGANIZATION: TERA BIOTECHNOLOGY CORPORATION TITLE SELECTION OF ANTIBODY FRAGMENTS WITH IMPROVED STABILITY ABSTRACT: Antibodies are routinely used in numerous diagnostic kits to yield specific reliable and fast assays. However, most antibody based diagnostic kits require some special conditions for storage, such as refrigeration, due to the instability of proteins at temperatures above 38 degrees Centrigrade. This Phase I application proposes experiments which are designed to identify thermostable antibodies that will maintain activity when exposed to long periods of elevated temperatures. Thermostable antibodies would have an advantage over conventional antibodies in that they can be stored, and used, in extreme field conditions.