Multi-drug resistant bacterial infections present an enormous ongoing challenge and infections now occur that are resistant to all current antibacterial options. The pipeline of novel therapeutics to treat drug-resistant infections, especially those caused by Gram-negative pathogens, is all but dry. To combat these multi-drug resistant pathogens, we present an approach that employs mixed ligand-modified gold nanoparticles (1 nm - 5 nm diameter) as antibiotics. Preliminary results indicate that our unoptimized nanoparticles are more potent than many small-molecule antibiotics against K. pneumoniae and E. coli, have essentially equivalent activity against MDR strains of these bacteria, and are less susceptible to evolution of resistance than small-molecule drugs. Preliminary murine studies have also shown no in vivo toxicity. Herein we propose to establish nanoscale structure-activity relationships (NSAR) of active nanoparticles and the mechanistic basis by which these particles inhibit bacterial growth. This information will be employed to optimize our antibiotic nanoparticles and develop new nanoparticles with broad-spectrum activity against all four classes of the Gram-negative ESKAPE pathogens. The in vivo potential of active nanoparticle antibiotics will be established in a murine model of infection.
The Center for Disease Control estimates that each year 2 million people in the US will acquire an infection while in a hospital, resulting in 100,000 deaths and $30 billion of direct costs. Multi-drug resistant bacterial infections present an enormous ongoing challenge and infections now occur that are resistant to all current antibacterial options. The pipeline of novel therapeutics to treat drug-resistant infections, especially those caused by Gram-negative pathogens, is all but dry. There is an urgent, immediate need for new treatments for these panresistant organisms and there is no evidence that this need will be met in the foreseeable future. This has prompted the Infectious Diseases Society of America (IDSA) to issue a call for action from the medical community to provide solutions to this problem. Our labs have used a new combinatorial synthesis and screening approach to identify ligand-modified gold nanoparticles with potent activity toward bacterial growth inhibition. The goal of this projec is to determine the mechanism(s) of activity so that optimized formulations may be advanced for use in an animal model of infection.
|Melander, Roberta J; Zurawski, Daniel V; Melander, Christian (2018) Narrow-Spectrum Antibacterial Agents. Medchemcomm 9:12-21|
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|Gifford, Jennifer C; Bresee, Jamee; Carter, Carly Jo et al. (2014) Thiol-modified gold nanoparticles for the inhibition of Mycobacterium smegmatis. Chem Commun (Camb) 50:15860-3|