Sensitization of gram‐negative bacteria by targeting the membrane potential. Issue 9 (3rd June 2013)

• Record Type: Journal Article
• Authors: Goldberg, Keren; Sarig, Hadar; Zaknoon, Fadia; Epand, Raquel F.; Epand, Richard M.; Mor, Amram
• Is Part Of: FASEB journal. Volume 27:Issue 9(2013)
• Page Start: 3818
• Page End: 3826
• Publication Date: 2013-06-03
• Subjects: proton motive force -- host defense peptides -- oligo‐acyl‐lysyl -- peptidomimetics -- synergy; Biology -- Periodicals; Biology, Experimental -- Periodicals; 570
• DOI: 10.1096/fj.13-227942
• Languages: English
• ISSNs: 0892-6638

Abstract

Abstract : Toward generating new tools for fighting multidrug‐resistant (MDR) bacteria, we assessed the ability of a membrane‐active peptide to sensitize gram‐negative bacteria to various antibiotics. The mechanism for affecting inner and/or outer membrane functions was assessed by complementary biophysical methods (SPR, DSC, ITC). The implication of efflux pumps was examined using Acr‐AB mutants, as tested with representative antibiotics, host defense peptides, and synthetic mimics. The ability to affect disease course systemically was compared for a single therapy and combination therapy, using the mouse thigh‐infection model. The data show that potent antibiotic action can be provoked in vitro and in vivo, by a treatment combining two antibacterial compounds whose individual inefficiency against gram‐negative bacteria stems from their efflux. Thus, at subminimal inhibitory concentrations, the lipopeptide‐like sequence, N α (ω7)dodecenoyl‐lysyl‐[lysyl‐aminodode‐canoyl‐lysyl]‐amide (designated C12 (ω7)K‐β12 ), has, nonetheless, rapidly achieved a transient membrane depolarization, which deprived bacteria of the proton‐motive force required for active efflux. Consequently, bacteria became significantly sensitive to intracellular targeting antibiotics. Collectively, these findings suggest a potentially useful approach for expanding the antibiotics sensitivity spectrum of MDR gram‐negative bacteria to include efflux substrates.—Goldberg, K., Sarig, H., Zaknoon, F., Epand, R. F., Epand, R. M., Mor, A., Sensitization of gram‐negative bacteria by targeting the membrane potential. FASEB J. 27, 3818–3826 (2013). www.fasebj.org