Scientific Abstract
Proposal No. IBD-0233
Principal Investigator: Michael T. Collins, D.V.M., Ph.D.
Applicant Organization: University of Wisconsin, Madison (U.S.A.)
Project Title: Evidence-based selection of antibiotics for treatment of Crohn's disease
Period of Award: January 1, 2008 – February 28, 2009
Mycobacterium avium subsp. paratuberculosis (MAP) is associated with Crohn’s disease (CD) [odds ratio 7.01, 95% CI 3.95 – 12.4]. Numerous Crohn’s disease patients have been exposed to potent antibiotics believed to be effective against (MAP) with mixed results. This proposal will provide critical, new data to identify the best therapeutic choices for anti-MAP treatment of CD patients. It will also show whether the concomitant use of immunosuppressive drugs compromises the anti-MAP activity of those antibiotics. We will partner with an innovative private firm that focuses on the discovery and development of anti-mycobacterial drugs
(Sequella).
This work will provide preliminary drug selection guidance to gastroenterologists, and ultimately may attract both public and private funding to support expanded drug testing and therapeutic trials in animal models.
Specific questions to be addressed:
- Which antimicrobials are most likely to kill or suppress the growth of MAP?
- Do the commonly used immunosuppressive drugs, 6MP and AZA, compromise antibiotic efficacy when used concomitantly to treat CD patients?
- Do novel proprietary drugs in the ethambutol compound family from Sequella that have been tested against other mycobacteria have anti-MAP activity?
Methodology:
Using the MGIT 960 ParaTB system the minimal inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of multiple drugs against MAP will be defined. A total of 10 human-origin low-passage clinical MAP strains will be used in this study. Ten commercial antimicrobials will be tested: isoniazid, rifampin, rifabutin, clofazamine, ethambutol, dapsone, azithromycin, ciprofloxacin, levofloxacin, and amikacin. Drugs showing anti-MAP activity will then be tested in combination with two immunosuppressive drugs: 6MP and AZA. An additional 10 novel and promising (per preliminary in vitro and in vivo data of activity against other mycobacteria) ethambutol derivatives will be evaluated as well. They will be selected from an extensive library of ethambutol compounds developed through combinatorial chemistry by Sequella.
Anticipated outcomes:
- The most comprehensive assessment of the human-origin MAP antimicrobial susceptibility profile.
- Essential MAP drug susceptibility data for clinical trials that will enable physicians to choose the most effective therapies.
- A short list of promising drugs and dosages to progress to further stages prior to clinical trials; ex vivo (infected macrophages) and animal trials.
- Demonstration of a novel system for direct evaluation of new anti-MAP drugs showing promise by high throughput screening assays.