Sensitization of Gram-Negative Bacilli to Host Antibacterial Proteins

To address the need for novel alternatives to antibiotics, we attempted to sensitize gram-negative bacilli to innate antibacterial protagonists. We report a lipopeptide-like sequence (C10OOc12O) that inflicted outer membrane damage at a low micromolar range, whereas measurable bacterial growth inhibition in broth medium required >10-fold higher concentrations. In serum, however, C10OOc12O induced antibacterial activity in a manner suppressible by anticomplement antibodies or heat treatment and acted synergistically with exogenous lysozyme in broth and serum media. Upon subcutaneous administration, C10OOc12O exhibited high circulating levels that correlated with significant therapeutic efficacies, using either the mouse peritonitis-sepsis model or the thigh infection model. These findings are consistent with the view that, by damaging the outer membrane, C10OOc12O was able to enhance gram-negative bacilli susceptibility to antibacterial components of the immune humoral arm. Such lipopeptides may therefore be useful in fighting gram-negative bacilli threats through sensitization to endogenous and/or exogenous antibacterial proteins such as lysozyme and complements.