Poster Presentation 11th Annual Conference of the International Chemical Biology Society 2022

SELENIUM - the superelement against superbugs? (#126)

Louise Friberg 1 , Karl A. Hansford 1 , Mark A.T Blaskovich 1 , Joanne Blanchfield 1
  1. University of Queensland, St Lucia, QLD, Australia

Due to overuse and misuse, less than a century since the discovery of the first antibiotic, we now face the looming threat of a post-antibiotic era with antimicrobial resistance (AMR) on the rise1. The WHO has predicted that the death toll due to AMR will rise to 10 million annually by 2050 if no action is taken2,3. With no new classes of antibiotics discovered since 1984, the discovery of novel antimicrobial agents is of paramount importance3.  

The Community for Open Antimicrobial Drug Discovery (CO-ADD) provides a free screening service for researchers to test the activity of compounds against ESKAPE pathogens4. To date, CO-ADD has screened over 310,000 compounds from 310 research groups in 48 countries resulting in 2,798 hits that are effective antimicrobials at concentrations non-toxic to human cells in vitro.

Analysing the entire CO-ADD library based on potency, synthetic tractability, and novelty, 206 organoselenium compounds were identified that displayed antimicrobial activity against Gram-positive bacteria and fungi. Of these compounds, 77 qualified as active with a minimum inhibitory concentration of < 16 µg mL-1 against at least one out of the seven CO-ADD microbes, representing a 37% hit rate, significantly higher than the over-all hit rate of 1.6% across the whole library. These organoselenium compounds also display reduced cytotoxicity and haemolytic activity against human embryonic kidney cells (HEK 293) and human red blood cells in comparison with the rest of the library (34% vs 65% of compounds showing HEK293 CC50< 32 µg mL-1 and haemolytic HC10< 32 µg mL-1). These organoselenium compounds also consistently displayed antifungal activity, suggesting the inclusion of selenium within organic scaffolds introduces a novel antifungal modality.

These results prompted the development of novel antimicrobials with organoselenium motifs with the aim to develop compounds displaying antifungal activity. Within this work we have synthesised modified pre-existing scaffolds that demonstrate some level of antimicrobial activity and included one or more selenium atoms to enhance the activity and lower toxicity

  1. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet 2022, 399 (10325), 629-655.
  2. OECD (2018), Stemming the Superbug Tide: Just A Few Dollars More, OECD Health Policy Studies, OECD Publishing, Paris
  3. Butler, M. S.; Gigante, V.; Sati, H.; Paulin, S.; Al-Sulaiman, L.; Rex, J. H.; Fernandes, P.; Arias, C. A.; Paul, M.; Thwaites, G. E.; Czaplewski, L.; Alm, R. A.; Lienhardt, C.; Spigelman, M.; Silver, L. L.; Ohmagari, N.; Kozlov, R.; Harbarth, S.; Beyer, P., Analysis of the clinical pipeline of treatments for drug resistant bacterial infections: despite progress, more action is needed. Antimicrobial Agents and Chemotherapy 0 (ja), AAC.01991-21.
  4. Hansford, K. A.; Blaskovich, M. A.; Cooper, M. A., Chemical philanthropy: a path forward for antibiotic discovery? Future Medicinal Chemistry 2016, 8 (9), 925-929.