Discovery and characterisation of novel ribosome-targeting antibiotics

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The ribosome and protein synthesis represent one of the major targets within the bacterial cell for inhibition. Many clinically important classes of antibiotics target the ribosome, however, multi-drug resistance of pathogenic bacteria has limited their utility, emphasizing the desperate need to develop novel antimicrobials that overcome the antibiotic-resistance pathogens. The majority of compounds in the development pipeline and in clinical trials are semi-synthetic derivatives of currently used antibiotics and are based on the chemical scaffold of the natural product progenitor compound. Therefore, it is desirable to discover and develop new antimicrobial agents that are based on completely new and unrelated chemical scaffolds and that have distinct binding sites on the target to avoid cross-resistance with currently used antibiotics. This proposal employs a validated fluorescence reporter system to screen for novel antimicrobial agents, with preliminary results already leading to the discovery of two novel scaffolds. Structural studies will be conducted to ascertain the binding site of these compounds on the ribosome, which will aid design, synthesis and screening of second generation derivatives. In addition, we have initiated structural analysis of a range of poorly characterized ribosome-targeting antibiotics that have distinct chemical scaffolds and therefore may target unique binding sites on the ribosome. In conjunction with a range of in vitro biochemical assays, our studies will also provide not only mechanistic insight into the mode of action of these compounds, but also shed light onto the fundamental process of protein synthesis.