Donald C. Hall, Jr., Ph.D.
Assistant Professor, Department of Microbiology and Immunology
Drexel University College of Medicine
(Early Career Symposium sponsored by ASM Young Ambassadors Program)

“Outsmarting Pathogens: Navigating the Frontier of Drug Discovery with Stringent Response Inhibitors”

The bacterial stringent response, a highly conserved mechanism for bacterial resistance, is controlled by the secondary metabolite (p)ppGpp, known as the magic spot alarmone. This alters cells through transcriptional processes involving RpoS, nucleotide pools, PolyP levels, and direct interaction with RNA Polymerase. Housekeeping of the magic spot alarmones is managed by enzymes RelA and SpoT, falling under the RSH superfamily. RelA and SpoT respond to stresses, influencing (p)ppGpp levels. The stringent response is important as a drug target due to its effects on bacterial quiescence, making bacteria metabolically resistant to antibiotics, and on virulence and toxin production. Disrupting the response reduces resistance and virulence. Our approach involves in silico screening of 5 million compounds, followed by in vitro and in vivo assays to identify effective “hit compounds.” Stage 2 involves a Structure Activity Relationship study, using empirical data to design new compounds. Our team has developed a RelA inhibitor effective against both Gram-positive and Gram-negative bacteria, targeting the stringent response.