The growing threat of drug-resistant bacteria, particularly among the Gram-negative members of the ESKAPE 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 (WP1). 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 (WP2). Moreover, we will examine the ability of the best synergistic combinations identified to reduce the occurrence of so-called “heteroresistance” (WP3).
The results to be delivered upon completion of this project are expected to be of great value in addressing antibiotic resistance among Gram-negative pathogens. In addition to uncovering new and effective combination therapies (WP1 and WP3), our findings will also have a transformative effect on the way that in vitro antibiotic activity is measured (WP2). Importantly, the aims described within this proposal are strengthened by encouraging preliminary data. The project also benefits from the involvement of Synamp Pharmaceuticals BV (www.synamp-pharma.com), a Dutch biotechnology company recently founded with the goal of developing new antibiotic strategies to counter resistant pathogens. Furthermore, the deliverables outlined in this proposal are envisioned to be achieved with the five-year timeframe upon completion of the project as indicated in the ZonMw ABR programme call.