The resistance of clinical infections is one of the fastest growing issues in the medical field today. A large number of these resistant infections can be attributed to biofilms. It is estimated that 80% of infections have some biofilm related aspect to them. These biofilms can be defined as a surface adhered aggregate of cells surrounded by a protective matrix. Biofilms are capable of collective antibiotic resistance. Because of the large role that biofilms play in clinical infections it is imperative to find a way to inhibit biofilm formation and induce biofilm degradation; this would subsequently re-potentiate antibiotics. This research focuses on the design and testing of small molecule inhibitors for the enzymes RelA and RSH (RelA/SpoT homologs). RelA and RSH are ATP:GTP(GDP) pyrophosphate transferases that control the synthesis of the stringent response triggering “magic spot” alarmones. “Magic spot” alarmones are hyperphosphorylated nucleotides (guanosine pentaphosphate and guanosine tetraphosphate). These alarmones induce a major change in cellular metabolism whereby the bacteria are converted into persister cells. These persister cells have upregulated some genes (such as chaperones, toxin/antitoxin systems and oxidative stress protection) and downregulated genes involved in cell wall synthesis, translation and DNA replication. All these factors make them up to a 1000x more resistant to antibiotics than their planktonic counterparts. The use of computational models, organic synthesis, and<i> in vivo</i> and in<i> vitro</i> assays have been employed to produce and evaluate lead compound inhibitors. These compounds have been successfully tested for their ability to interrupt the stringent response as well as re-potentiate antibiotics for the treatment of infectious bacteria.

Design and development of small molecule RelA/RSH inhibitors

256th National Meeting (2018)

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