Nanoparticle decoys for treating infections with enterotoxin-producing pathogens - Intestinal infections with enterotoxin-producing pathogens, such as Vibrio cholerae, enteroxigenic
Escherichia coli (ETEC), Shiga toxin-secreting E. coli (STEC), and Shigella dysenteriae, are major worldwide
causes of diarrheal and not infrequently severe systemic disease. Treatment with conventional antibiotics is
often ineffective, compromised by resistance, or contraindicated. The enterotoxins produced by these
pathogens are central in disease pathogenesis, since mutation of the toxins or their host receptors markedly
attenuates or abolishes disease. Because of their critical role, the respective host receptors constitute
attractive targets for non-traditional antimicrobial strategies that do not rely on conventional antibiotics,
because the receptors, contrary to any bacterial factors, are constant and do not mutate over therapeutically
relevant time frames, eliminating concerns about antibiotic resistance development. One major approach to
leverage host receptor specificity is the development of pharmacological decoys that are identical to and
compete with the receptors, and thus act as harmless sinks or sponges for the toxins until they are removed or
destroyed by the host. This decoy strategy has been successfully tested in animal models using geneticallymodified
commensal bacteria as decoys, but a chemical drug candidate based on the same principle has not
proven effective in a clinical trial of STEC infection. A key difference between these approaches is the receptor
density of the decoys, with engineered bacteria displaying >1,000 greater surface receptor abundance and
presumably better affinity than chemical agents. However, genetically altered, live microorganisms are
problematic as therapeutics, as they are difficult to produce at pharmaceutical grade, hard to tailor, prone to
mutate, and potentially colonize the host permanently and even cause disease. As an alternative, we propose
to develop hybrid nanoparticles as decoys that display high density of toxin receptors on the surface, but are
amenable to design modifications and can be readily produced under pharmaceutically desirable conditions.
The project consists of two phases. In the milestone-driven exploratory R21 phase (Aim 1), we will develop a
novel nanotechnology platform using cholera toxin as model toxin, and conduct in vitro and in vivo tests of
nanoparticle activity. In the subsequent expanded development R33 phase (Aims 2 and 3), we will explore the
capacity of nanoparticle decoys to protect against live V. cholerae in vitro and in vivo, and apply the
nanoparticle strategy to other enterotoxins and their pathogens, ETEC, STEC, and S. dysenteriae. Together,
the proposed project will develop a novel nanotechnology-based platform as a non-traditional antimicrobial
strategy for the management of intestinal infections with enterotoxin-producing pathogens that cannot be
treated with conventional antibiotics due to resistance or other biological reasons.
