Eliciting improved antibacterial efficacy of host proteins in the presence of antibiotics.

We recently reported the aptitude of a membrane-active lipopeptide (COOcO) to sensitize gram-negative bacilli (GNB) to host antibacterial proteins. Here we explored the potential of harnessing such capacity in the presence of antibiotics. For this purpose, we compared sensitization to antibiotics in broth and plasma; assessed inner and outer membrane damages using scanning electron microscopy, dyes, and mutant strains; and assessed the ability to affect disease course using the mouse peritonitis-sepsis model for mono- and combination therapies. We found that by altering permeability of both outer and inner membranes, subinhibitory concentrations of COOcO can transiently sensitize GNB to diverse cytoplasm-targeting antibiotics in simple media. Sensitization was maintained in plasma, where COOcO instigated greater bactericidal activities, including in the presence of a bacteriostatic antibiotic (erythromycin). Single-dose administrations of rifampin and COOcO to -infected mice resulted in 55% 0, and 36% viability, respectively, for combined and individual treatments. Combining COOcO and erythromycin has similarly improved mice protection from developing fatal sepsis. Consequently, the data confirmed that COOcO renders GNB sensitive to both endogenous and exogenous antibacterials, and suggested that the tripartite concomitant presence increases therapeutic efficacy synergistically. This approach might expand the available treatment options to comprise antimicrobials with low permeability and/or efflux issues.-Jammal, J., Zaknoon, F., Mor, A. Eliciting improved antibacterial efficacy of host proteins in the presence of antibiotics.