BET Inhibitors: Novel Approaches to Combatting Antimicrobial Resistance

Pollard, Hollie Mae (2025) BET Inhibitors: Novel Approaches to Combatting Antimicrobial Resistance. Masters by Research thesis (MSc), Manchester Metropolitan University.

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Abstract

Antimicrobial resistance is an increasing global threat and there is an urgent need for new antimicrobial therapeutics, specifically against multi-drug resistant bacteria. One approach is to use small molecule inhibitors (SMIs) to target specific pathogen virulence traits. BET inhibitors are a type of SMI that target BET proteins, which regulate transcription by reading the acetylation of the lysine residues on histone tails. This study is the first report where the BET inhibitor (+)-JQ1 has been deployed as an antimicrobial agent. The antimicrobial activity of the (+)-JQ1 SMI was identified from a screening plate containing various SMIs and this showed activity against a multidrug resistant strain of Staphylococcus aureus strain USA300 at <456.99 μg mL-1. The Minimum Inhibitory Concentration (MIC) of the biologically active form of (+)-JQ1 against this strain was 128 μg mL-1, while the MIC of the stereoisomer derivative (-)-JQ1 was 125 μg mL-1. The similarity between these two results, coupled with the lack of BET protein homologues within S. aureus led to the hypothesis that the mechanism of antimicrobial action being observed was an off-target effect of the compound. SMI (+)-JQ1 was found to target some of the key virulence factors of S. aureus through the inhibition of biofilm formation and haemolytic toxin production. While no cellular morphological changes were observed after bacterial (+)-JQ1 exposure, this SMI was found to depolarise the membrane of S. aureus strain USA300 offering an insight into the potential antimicrobial mechanistic activity. This research demonstrated a novel off-target antimicrobial application of the BET inhibitor (+)-JQ1 and the stereoisomer (-)-JQ1. There is potential for this SMI to be explored further as a topical wound dressing or wound cleaning agent against the multidrug resistant pathogen S. aureus.