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Antimicrobial Agents and Chemotherapy, April 2006, p. 1245-1250, Vol. 50, No. 4
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.4.1245-1250.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Rapid Microbiologic and Pharmacologic Evaluation of Experimental Compounds against Mycobacterium tuberculosis

Veronica Gruppo,1 Christine M. Johnson,1 Karen S. Marietta,1 Hataichanok Scherman,1 Erin E. Zink,1 Dean C. Crick,1 Linda B. Adams,2 Ian M. Orme,1 and Anne J. Lenaerts1*

Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado 80523,1 National Hansen's Disease Program, Baton Rouge, Louisiana2

Received 27 May 2005/ Returned for modification 17 August 2005/ Accepted 31 January 2006

The assessment of physiochemical and pharmacological properties at early stages of drug discovery can accelerate the conversion of hits and leads into candidates for further development. A strategy for streamlined evaluation of compounds against Mycobacterium tuberculosis in the early preclinical stage is presented in this report. As a primary assay to rapidly select experimental compounds with sufficient in vitro activity, the growth inhibition microtiter plate assay was devised as an alternative to current methods. This microdilution plate assay is a liquid culture method based on spectrophotometric readings of the bacillary growth. The performance of this method was compared to the performance of two established susceptibility methods using clinical available tuberculosis (TB) drugs. Data generated from all three assays were similar for all of the tested compounds. A second simple bioassay was devised to assess the oral bioavailability of compounds prior to extensive in vivo efficacy testing. The bioassay estimates drug concentrations in collected serum samples by a microdilution MIC plate method using M. tuberculosis. In the same assay, the MIC of the compound is also determined in the presence of 10% mouse serum as an indication of protein binding. The method was validated using different clinically available TB drugs, and results are discussed in this report. With these methodological advances, screening of compounds against tuberculosis in the preclinical phase will be rapid, can be adapted to semi-high-throughput screening, and will add relevant physicochemical and basic pharmacological criteria to the decision process of drug discovery.

* Corresponding author. Mailing address: Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523. Phone: (970) 491-3079. Fax: (970) 491-5125. E-mail: lenaerts{at}colostate.edu.

Antimicrobial Agents and Chemotherapy, April 2006, p. 1245-1250, Vol. 50, No. 4
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.4.1245-1250.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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