New approaches to target antibacterial agents toward Gram -negative bacteria are key, given the rise of antibiotic resistance. Since the discovery of polymyxin B nonapeptide as a potent Gram... Show moreNew approaches to target antibacterial agents toward Gram -negative bacteria are key, given the rise of antibiotic resistance. Since the discovery of polymyxin B nonapeptide as a potent Gram-negative outer membrane (OM)-permeabilizing synergist in the early 1980s, a vast amount of literature on such synergists has been published. This Review addresses a range of peptide-based and small organic compounds that disrupt the OM to elicit a synergistic effect with antibiotics that are otherwise inactive toward Gram -negative bacteria, with synergy defined as a fractional inhibitory concentration index (FICI) of <0.5. Another requirement for the inclusion of the synergists here covered is their potentiation of a specific set of clinically used antibiotics: erythromycin, rifampicin, novobiocin, or vancomycin. In addition, we have focused on those synergists with reported activity against Gram-negative members of the ESKAPE family of pathogens namely, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, and/or Acinetobacter baumannii. In cases where the FICI values were not directly reported in the primary literature but could be calculated from the published data, we have done so, allowing for more direct comparison of potency with other synergists. We also address the hemolytic activity of the various OM-disrupting synergists reported in the literature, an effect that is often downplayed but is of key importance in assessing the selectivity of such compounds for Gram-negative bacteria. Show less
Extending our current arsenal of antibiotics is key to staying ahead in the arms race between humans and resistant bacteria. Classes of antibiotics otherwise limited to the treatment of Gram... Show moreExtending our current arsenal of antibiotics is key to staying ahead in the arms race between humans and resistant bacteria. Classes of antibiotics otherwise limited to the treatment of Gram-positive pathogens may be potentiated against Gram-negative bacteria by disruption of their outer membrane. The work described in this thesis focuses on the development of novel synergists designed to selectively disrupt the outer membrane and in doing potentiate the activity of antibiotics that are otherwise inactive against Gram-negative bacteria. Show less
