Repurposing human kinase inhibitors to create an antibiotic active against drug-resistant Staphylococcus aureus, persisters and biofilms

Abstract

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Degrasyn exhibits antibiotic activity against multi-resistant Staphylococcus aureus by modifying several essential cysteines

“…1B). 5,11 Satisfyingly, the antibiotic activity was retained in all MRSA strains (MIC r 12.5 mM) suggesting a different mode-of-action as compared to existing drugs.…”

“…Therefore, due to availability of building blocks and synthetic accessibility, we studied substituted phenyl rings at this position in more detail. Bromine-and chlorine-substituted phenyl rings were able to largely maintain antibiotic effects (5,6,7). In contrast, fluoro-and iodo-substituted phenyl rings resulted in a loss of activity (8,9,10).…”

“…1,2 One strategy to identify novel antibacterials focuses on the repurposing of existing drugs originally developed against human proteins. 3,4 In a recent drug-repurposing screen, 5 we identified that the human deubiquitinating enzyme inhibitor degrasyn (also called WP1130) kills methicillin-sensitive S. aureus (MSSA) ( Fig. 1A and B).…”

“…While an unsubstituted pyridine ring led to a loss of antibiotic activity (1, 2), varying the positions of the bromine substituent and the nitrogen atom was tolerated with only a slight loss in activity (3,4). Even the replacement of the pyridine ring with a phenyl ring retained considerable activity (5). Therefore, due to availability of building blocks and synthetic accessibility, we studied substituted phenyl rings at this position in more detail.…”

Repurposed anti-cancer drugs: the future for anti-infective therapy?

“…These compounds act through a new mechanism involving stimulation of the signal peptidase SpsB which regulates protein secretion, leading to an increase in the secretion of peptidoglycan hydrolase (PGH)domain-containing proteins and hence promoting autolysis. Furthermore, they kill persister cells, and the continuous exposure of S. aureus to PK150 during 27 daily passes failed to induce resistance, making this drug a robust antibacterial [21].…”