The broad, long-term objectives of this research program are to develop new methods and systems to probe fundamental molecular recognition and catalytic phenomena and with which to test a novel concept in therapeutic design: that antibiotic derivatives which act catalytically against their targets will exhibit enhanced potency relative to antibiotics which combine with the same targets stoichiometrically.
Specific aims of the research described in this application are to 1) extend and refine efficient and selective methods developed in the PI's laboratory for the semisynthetic modification of vancomycin, and 2) prepare and study novel semisynthetic vancomycin derivatives that catalyze the cleavage of peptidoglycan precursor analogs. Vancomycin carboxamides bearing catalytic functional groups or siderophores will be prepared by semisynthetic elaboration of the parent antibiotic. Biochemical, biophysical, and microbiological methods will be used to test the abilities of these compounds to bind to cell wall precursor peptides, to effect the chemical transformation of precursor substrates, and to exert antibacterial effects. The timeliness of this proposal is reflected in the current realization that novel and improved antibiotics and therapeutic approaches will be needed to meet the serious threats to health posed by the advent of multiply drug-resistant and virulent bacterial pathogens. The relevance of the proposed work to health derives from its focus on developing and testing novel medicinal chemistry concepts in the context of addressing specific drawbacks, limitations, and challenges to the clinical usefulness of vancomycin, including its potency-limiting stoichiometric mode of action, its ineffectiveness against gram-negative organisms, and the emergence of vancomycin-resistant enterococci.
