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bioRxiv · 10.1101/2020.01.06.896498

Antimicrobial activity of the quinoline derivative HT61, effective against non-dividing cells, in Staphylococcus aureus biofilms

Frapwell, C. J.·Skipp, P. J.·Howlin, R. P.·Angus, E. M.·Hu, Y.·Coates, A. R.·Allan, R. N.·Webb, J. S.
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Abstract

Staphylococcus aureus is an opportunistic pathogen responsible for a wide range of chronic infections. Disease chronicity is often associated with biofilm formation, a phenotype that confers enhanced tolerance towards antimicrobials, a trait which can be attributed to a dormant, non-dividing subpopulation within the biofilm. Development of antibiofilm agents that target these populations could therefore improve treatment success. HT61 is a quinoline derivative that has demonstrated efficacy towards non-dividing planktonic Staphylococcus spp. and therefore, in principal, could be effective against staphylococcal biofilms. In this study HT61 was tested on mature S. aureus biofilms, assessing both antimicrobial efficacy and characterising the cellular response to treatment. HT61 was found to be more effective than vancomycin in killing S. aureus biofilms (minimum bactericidal concentrations: HT61; 32 mg/L, vancomycin; 64 mg/L), and in reducing biofilm biomass. Scanning electron microscopy of HT61-treated biofilms also revealed disrupted cellular structure and biofilm architecture. HT61 treatment resulted in increased expression of proteins associated with the cell wall stress stimulon and dcw cluster, implying global changes in peptidoglycan and cell wall biosynthesis. Altered expression of metabolic and translational proteins following treatment also confirm a general adaptive response. These findings suggest that HT61 represents a new treatment for S. aureus biofilm-associated infections that are otherwise tolerant to conventional antibiotics targeting actively dividing cells.

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Frapwell, C. J., Skipp, P. J., Howlin, R. P., Angus, E. M., Hu, Y., Coates, A. R., Allan, R. N., Webb, J. S.. 2020-01-07. Antimicrobial activity of the quinoline derivative HT61, effective against non-dividing cells, in Staphylococcus aureus biofilms. https://doi.org/10.1101/2020.01.06.896498

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