Antibiotic combination therapies against drug resistant Gram negative pathogens
Can effective synergists be identified to enhance the effect of antibiotics against Gram negative pathogens?
- 2017 - 2021
- Nathaniel Martin
The growing threat of drug-resistant bacteria, particularly the among the Gram-negative members of the ESKAPE group of pathogens, highlights the importance of developing new antibacterial strategies. This proposal is aimed at identifying approaches for using “Gram-positive specific” antibiotics that target the bacterial cell wall or inner membrane to also kill drug-resistant Gram-negative pathogens.
The outer membrane of Gram-negative bacteria presents a physical barrier to most antibiotics that target the bacterial cell wall or inner membrane. To address this limitation we will assess the ability of compounds known to disrupt the Gram-negative outer membrane to synergize with various glycopeptides, lipopeptides, and lantibiotics. In addition, we will evaluate the effect of such antibiotics in the presence of components of the human innate immune system known to permeabilize the Gram-negative outer membrane. Moreover, we will examine the ability of the best synergistic combinations identified to reduce the occurrence of so-called “heteroresistance”.