The Infectious Disease Society of America has named antimicrobial resistance the greatest global threat to human health. More than half of all infections are due to bacteria growing as biofilms, which are a community of cells enmeshed in a self-made matrix that can be up to 1000x more resistant conventional antimicrobials. Pseudomonas aeruginosa in particular, due to its numerous resistance mechanisms is a formable threat that often forms biofilms. Few new therapies have been developed to combat P. aeruginosa, and our antibacterial arsenal continues to decline. One solution to this daunting problem are anti-resistance compounds or adjuvants, which enhance conventional antimicrobials, extending and improving their utility. Here, we describe three adjuvants, triclosan, oxyclozanide and melittin. We demonstrate that each synergizes with tobramycin against mature P. aeruginosa biofilms. We also define the mechanism of action of triclosan and oxyclozanide, as protonophores that inhibit efflux pump activity, rendering cells susceptible to tobramycin killing. These adjuvants could be used in conjunction with current therapies to both improve their effectiveness, extend their lifespan, and target cells in biofilms
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