期刊
JOURNAL OF INFECTIOUS DISEASES
卷 215, 期 10, 页码 1599-1607出版社
OXFORD UNIV PRESS INC
DOI: 10.1093/infdis/jix119
关键词
Peptidomimetics; oligomers of acylated cations; synergy; antibiotic resistance; mechanism of action
资金
- Israel Science Foundation [909/12]
- Russell Berrie Nanotechnology Institute (Technion)
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 (C(10)OOc(12)O) 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, C(10)OOc(12)O 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, C(10)OOc(12)O 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, C(10)OOc(12)O 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.
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