Design, Synthesis, and Evaluation of Carbapenem and Cephalosporin Antibiotics to Counter Resistant 21st Century Pathogens

Antibiotics represent one of mankind’s most important discoveries, enabling longer, more productive lives. Carbapenem antibiotics are one of the most potent classes of β-lactams and often represent the last resort used to treat patients who are seriously stricken by bacterial infections. Carbapenems possess a broad spectrum of antibacterial activity including efficacy against the majority of Gram-positive and Gram–negative bacteria. Unfortunately, the emergence of antibiotic resistant strains is posing a serious threat to existing antibiotics. New discoveries in the antibiotic field are desperately needed to counter the threat of rapidly evolving bacterial resistance. Despite the investment of billions of dollars, and the elucidation of the bacterial genome, the past thirty years has seen extremely few new classes of antibiotics. All major pharmaceutical companies have now left the field of antibiotic discovery. Nearly a century after their initial discovery, the β-lactam class still accounts for more than half of prescribed antibiotics, with successive subclasses of β-lactams having been modified into as many as five separate generations to counter evolving bacterial resistance. This dissertation is focused on design, synthesis, and evaluation of novel atypically substituted (i. e. substituted at C6, C1) carbapenems and cephalosporins with the objective of establishing structure activity relationships (SARs) against 21st century pathogens, particularly including Mycobacterium tuberculosis, Mycobacterium abscessus, Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii. Working together with numerous collaborators, we will determine how changes in antibiotic structure can affect susceptibility to carbapenemases, ability to penetrate the outer membrane of Gram-negative pathogens, and ability to bind to the target transpeptidases of these microorganisms