This proposed research will address the urgent need for new strategies to fight bacterial infections of cystic fibrosis (CF) patients. CF patients are particularly susceptible to lung infections. The threat posed by gram negative pathogens, particularly of pseudomonas aeruginosa, requires the discovery and development of new antibiotic agents. This research will innovate an antibacterial agent that consists of a nanoparticle for the polyvalent presentation of polymyxin B (PB). Although PB remains one of the few antibiotics to which many problematic gram-negative pathogens remain susceptible, the utility of PB in the clinic is severely limited by a narrow therapeutic window. The maximum dose of PB tolerated by patients is suboptimal in efficacy and results in frequent clinical failures; further dose escalation is associated with unacceptably high rates of nephrotoxicity. Fulfilling the potential of PB in antibiotic therapy, one that exploits the ability of PB to damage the outer membrane of gram negative bacteria, requires the enhancement of potency and reduction of its nephrotoxicity. This research will develop a strategy that uses a nanoparticle formulation of PB to accomplish these goals. We will design and synthesize nanoparticle structures (NP-PB) that consist of a nanoparticle core that presents chemisorbed derivatives of polymyxin B at the surface of the nanoparticle at high density. The design of NP-PB is ideal for enabling the polyvalent binding of PB to the outer membrane of gram negative pathogens, and for generating an increase in localized damage to the outer membrane. In doing so, NP-PB will provide a way to enhance the potency of antibacterial activity of PB. Furthermore, our development of NP-PB will also alter the pharmacokinetic properties of PB, through our control of the size of NP-PB and the physico-chemical properties of the surface of NP-PB. The approach to this research will include 1) the design and synthesis of NP-PB and the analysis of its interactions with the outer membranes of gram negative bacteria; 2) the analysis of the pharmacokinetic properties, as a function of the structural properties of NP-PB; 3) evaluation of the efficacy of NP-PB in animal models of lung infection. Success in this research will establish that NP-PB can enhance the antibacterial activity of PB, identify designs of NP-PB that distribute to the lungs and have reduced distribution to the kidneys, and demonstrate efficacy in treating lung infections. Further development of a lead structure identified in this research will represent a therapeutic approach for treating acute or chronic infections of pseudomonas the CF lung, for which current clinically used antibiotic regimens fail to clear the bacteria.
|Effective start/end date||11/1/17 → 10/31/21|
- Cystic Fibrosis Foundation (LEE17GO)