Abstract.
Small molecule probes are critical to the investigation and treatment of human diseases. Our group is exploring
the basic biology of various human diseases (e.g., cancer, opioid addiction, malaria, bacterial biofilms) using
an array of new small molecule probes. During this award, we will advance our ring distortion platform using a
panel of readily available indole alkaloids as starting points for the dramatic altering of their complex ring
systems leveraging dearomative cycloadditions along with other chemoselective reactions. Active compounds
identified from our ring distortion platform have gained new biological functions as their activities are unrelated
to their parent natural product and other scaffolds. In essence, we have re-engineered the biological activities
of select indole alkaloids to study diverse disease states and now we aim to explore the modes of action
regarding these new probes. This basic (chemical synthesis) technology has served as a launching point to
discover and explore new biology in multiple disease areas. We will develop probes for transcript profiling
experiments and/or target identification expeditions, as necessary. In addition, we have identified a series of
halogenated phenazines (HP) that demonstrate potent antibacterial and biofilm-eradicating activities against
critical Gram-positive pathogens. These findings are significant as bacterial biofilms, or surface-attached
bacterial communities, house persistent, non-replicating bacteria (“persister cells”) that demonstrate tolerance
to all classes of antibiotics. Biofilms pose a significant threat to human health as 17 million new biofilm-
associated infections occur annually that result in 550,000 deaths in the United States. During this award, we
aim to expand the spectrum of activity for halogenated phenazine agents and eradicate Gram-negative
bacterial pathogens through the development of new phenazine-forming reactions to incorporate primary
amine moieties (following eNTRy rule guidelines) and develop HP-sideromycin agents to target specific Gram-
negative species. New biofilm-eradicating agents can provide critical insights into the basic biology of Gram-
negative biofilm cell viability and could lead to ground-breaking cures for persistent bacterial infections in the
future.