| The widespread use of antibiotics over the last 50 years has resulted in a dramatic and significant improvement in public health. Antibiotics discovered from the bacterial, plant and marine sources revolutionized health care and prompted many to believe that, in general, infectious disease would be eradicated. However, the misuse and overuse of antibiotics among other factors has led to the recent emergence of antibiotic-resistant infections. Herein we describe two approaches toward addressing this problem. In the first approach the powerful glycopeptide antibiotic vancomycin is covalently dimerized to produce novel olefinic and disulfide linked analogs with activity against several vancomycin-resistant strains. Furthermore, we explored the use of target-accelerated combinatorial synthesis to increase the efficiency of discovering potent olefin containing dimers. In a second approach to overcoming bacterial resistance, we explored the marine natural product psammaplin A. Utilizing a combinatorial disulfide exchange strategy we discovered many highly potent compounds capable of eradicating methicillin-resistant staphylococcus aureus strains. Additionally, some of these novel compounds are shown to be highly selective for bacterial cells over mammalian cells, paving the way for future development. Finally, we are able to dispute the claim that DNA gyrase is the primary site of action of this family of antibiotics. |
