The Search For New Antimicrobial Agents Against Mycobacterium abscessus,

Ref ID: 18774

Author:

M. A. De Groote, MD (Doctor of Medicine) – Asst Professor1, S. Cho, PhD – Professor 2, L. L. Klein, PhD – Professor 3, S. G. Franzblau, PhD – Professor 4;

Author address:

1Colorado State Univ., Fort Collins, CO, 2Univ. of Illiniois at Chicago, Chicago, IL, 3Univ. of Illinois at Chicago, Chicago, IL, 4Univ. of Illinois, Chicago, IL.

Full conference title:

52nd Annual ICAAC

Date: 9 September 2014

Abstract:

Background: Mycobacterium abscessus is an emerging pathogen which due to intrinsic antimicrobial drug resistance is a difficult infection to treat. High-throughput screens were conducted utilizing both known drugs and new/novel compound libraries in our search for growth inhibitory molecules. Methods: Using a validated and reproducible 3-day whole cell screening assay utilizing both ATP and Alamar Blue reduction readouts we screened the Prestwick library of known drugs for anti-M. abscessus activity and found several non-antibiotic agents with promising activity. In addition, we screened against M. abscessus over 2,000 M. tuberculosis (TB)-active compounds derived from high throughput screens at Southern Research Institute. We performed confirmatory MIC testing and in some cases assays for bactericidal activity. Results: Screening of the Prestwick library resulted in expected activity of known antibiotics and disinfectants but unexpected activity for some agents such as niclosamide, ivermectin, suloctidil, pyrvinium, naftifine, disulfiram, resveratrol, ebselen and rifabutin. The screening of a collection of libraries of TB actives revealed a disappointing hit rate vs. M. abscessus of less than 10%. We pursued several active agents and will pursue the mode of action of members of these series identified from the NIAID libraries. From these hits, several promising compounds and analogs from three separate series have been identified and these will be the subject of hit to lead work and potentially lead optimization efforts. Conclusions: Agents with activity against M. abscessus are hard to find likely due to a fairly impenetrable cell wall. However, despite this barrier, we have identified promising hits/leads and analogs of the most promising hits/leads are being pursued. Of the known drugs, the antifungal and CNS active agents are interesting candidates for future in vivo preclinical efficacy studies if the pharmacokinetic profiling is acceptable. Our work offers hope for new agents in the armamentarium against particularly challenging rapidly growing mycobacterial infections.

Abstract Number: F-831

Conference Year: 2012

Link to conference website: NULL

New link: NULL

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