Natural Product-Inspired Antibiotic Adjuvants for Gram-Positive and Gram-Negative Pathogens

Bacterial infections throughout history have played a formative role in humanity. Many of these infections were untreatable until the rise of the antibiotic age in the 1900’s. However, this golden age was short lived due to the natural development of resistance to nearly all clinically used antibiotics. Coupled with a dearth of new antibiotics, this resistance threatens to return healthcare to a pre-antibiotic state unless new tactics are identified to subvert antibiotic resistance. The work presented here focuses on several of the leading bacterial threats by developing natural-product inspired molecules that directly combat antibiotic resistance. The second chapter outlines efforts towards developing a marine alkaloid scaffold that is active against two different pathogens: as a biofilm inhibitor against the gram-positive bacterium Mycobacterium smegmatis, and as a potentiator of polymyxin antibiotics in the gram-negative pathogens Acinetobacter baumannii and Klebsiella pneumoniae. This work improved on previous work on this scaffold and identified two analogs with improved potency.

The rest of the document focuses on the total synthesis of a diterpene natural product that potentiates the b-lactam antibiotic oxacillin against methicillin-resistant Staphylococcus aureus. This pathogen is a leading cause of hospital acquired infections and the number of effective treatments is dwindling. The total synthesis confirmed the structure of the active natural product and allowed assignment of a previously unclear stereocenter. Additionally, screening against a transposon mutant library identified PBP2a as a potential target, though the exact relationship is currently unknown. Following this preliminary study, interrogation of the decalin motif demonstrated that small alterations aimed at simplifying the synthesis and improving properties were well-tolerated. Additionally, a new synthetic route was developed that cuts the number of steps to reach the target by almost half.