Ceragenins are small molecule mimics of endogenous antimicrobial peptides. They are broad-spectrum antimicrobial agents with activity against common and drug-resistant pathogens. Antimicrobial peptides play a central role in controlling bacterial growth in multiple tissues, including in the gastrointestinal tract. Antimicrobial peptides have been found in organisms ranging from humans to insects, and their ubiquity argues that they have evolved independently numerous times. This observation argues that the mechanism by which they eliminate bacteria provides a sustainable means of controlling bacterial growth. However, antimicrobial peptides are relatively difficult to prepare on a large scale and in general they are substrates for proteases. The ceragenins are relatively simple to prepare, and because they are not based on peptides, they are not substrates for proteases. In multiple direct comparisons of ceragenins and selected antimicrobial peptides, their mechanisms of action are indistinguishable. Intestinal infections kill millions of people annually, hinder the development of tens of millions of children, prolong hospital stays, increase mortality of hospitalized patients, and have become a concern as potential means of bioterrorism by contamination of water and food. The emergence of drug-resistant pathogens causing intestinal infections has added to this concern and has contributed to the call for new antimicrobials that will not engender resistance. The ceragenins are active against intestinal pathogens and are well- tolerated orally. Steps toward clinical use of the ceragenins include large-scale synthesis, formulation, toxicity and effacy studies. These steps are proposed. In addition, specific ceragenins display very high levels of activity against certain clinical isolates of Clostridium difficile, and it is expected that minor modifications to ceragenins will result in compound with broad, selective activity against this human pathogen. Studies of the interactions with membranes from C. difficile and a modest structure-activity study are proposed to better target ceragenins to C. difficile.

Public Health Relevance

Targeted organisms are Shigella spp. and C. difficile (including drug-resistant forms). The ceragenins are also active against the following organisms: E. coli, Vibrios, Salmonella, Listeria monocytogenes, Campylobacteria jejuni and Yersinia enterocolitica (all Category B Pathogens). The research and development of the ceragenins falls within the field of """"""""innate immunity"""""""" which is also listed in Class C.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI082209-03
Application #
8134342
Study Section
Special Emphasis Panel (ZAI1-MMT-M (J2))
Program Officer
Ranallo, Ryan
Project Start
2009-09-09
Project End
2014-02-28
Budget Start
2011-09-01
Budget End
2014-02-28
Support Year
3
Fiscal Year
2011
Total Cost
$1,467,735
Indirect Cost
Name
Brigham Young University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
009094012
City
Provo
State
UT
Country
United States
Zip Code
84602
Pollard, Jake E; Snarr, Jason; Chaudhary, Vinod et al. (2012) In vitro evaluation of the potential for resistance development to ceragenin CSA-13. J Antimicrob Chemother 67:2665-72
Epand, Raquel F; Pollard, Jake E; Wright, Jonathan O et al. (2010) Depolarization, bacterial membrane composition, and the antimicrobial action of ceragenins. Antimicrob Agents Chemother 54:3708-13