Structure based drug discovery for the development of small molecule RelA inhibitors

Md Rumman Uz Zaman

doi:10.17918/00011219

Antimicrobial resistance poses a significant challenge to global public health, leading to decreased antibiotic efficacy. Overuse or misuse of antibiotics fosters bacterial tolerance, allowing microorganisms to survive harsh environments like nutrient deprivation. One such mechanism is the formation of biofilms through persister cells. Escherichia coli (E. coli) is known for causing chronic infections and forming biofilms that contribute to antibiotic treatment failure. The signal molecule (p)ppGpp plays a crucial role in E.coli's stringent response, which contributes to the biofilm formation. One (p)ppGpp synthetase, RelA is of particular importance due to its role in regulating (p)ppGpp levels within the bacteria. Targeting RelA, a key enzyme in (p)ppGpp synthesis, has emerged as a promising strategy for the development of novel antibiotics. So far, there have been very few attempts to develop small-molecule inhibitors of RelA. Our lab has previously reported a handful of small-molecule RelA inhibitors with limited activity. In this study, we aimed to design, synthesize, and evaluate more potent small-molecule inhibitors of RelA through a structure-based drug design (SBDD) approach on a much larger scale than earlier studies. We investigated the inhibitory potential of over half a million small molecules available in online databases, and selected top compounds based on their high predicted binding affinities, as assessed by AutoDock Vina. Afterward, we generated additional structures by modifying the initial hit compounds based on their protein-ligand interactions. Molecular Dynamics (MD) simulation has been performed to evaluate the stability of the highest-scoring modified structures. Next, we synthesized some of the structures obtained from our computational studies and tested them in vitro against RelA to investigate their activity using a more precise method than the previously reported one. In vitro assays demonstrated moderate inhibition of ppGpp production by several compounds, consistent with computational predictions. This work supports the potential of these newly synthesized analogues as RelA inhibitors and highlights their relevance in future antibacterial drug development efforts.

Structure based drug discovery for the development of small molecule RelA inhibitors

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Structure based drug discovery for the development of small molecule RelA inhibitors

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