Medical biofilms can be defined as an infectious organized community of bacteria that are living as a multicellular entity. Bacteria have evolved a strategy to ensure their survival in these communities. This strategy is called the “stringent response” and is activated almost universally among most bacterial species. The keystone enzyme in the process of metabolic quiescence of bacteria is RelA. RelA is a highly conserved pyrophosphotransferase that is encoded by the relA gene. This enzyme is responsible for sensing amino acid starvation and is self-regulating within a bacterial biofilm. RelA catalyzes the reaction between GTP and ATP to form the “alarmones” pppGpp (guanosine pentaphosphate) and ppGpp (guanosine tetraphosphate). These molecules trigger a transcriptional change within the cell causing an upregulation in oxidative damage combating enzymes as well as a reduction in replication machinery. Cells that have gone through these metamorphic changes are called persister cells. Persister cells, while not genetically resistant to antibiotics, can withstand up to 1000x the antibiotic concentrations of their planktonic counterparts. This work outlines our task of developing a RelA inhibitor which would both prophylactically stop persister cells formation and would convert already formed persister cells to their susceptible state allowing for the synergetic treatment of medical biofilms. Our lab has taken an <i>in silico </i>pipeline approach to determine hit compounds for the inhibition of RelA. Using this approach, and our multidisciplinary ideals, we have taken these <i>in silico</i> hit compounds and have shown its effectiveness in inhibiting RelA and biofilm persistence. We have developed and synthesized several analogs of our hit compounds and have tested them in SAR studies to show how these compounds interact in the inhibition of the RelA enzyme. Through this approach, we have gained both a better understanding of the stringent response and the ability to combat bacteria in medical biofilm infections.

Development and design of RelA/RSH inhibitors for the treatment of medical biofilms

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.