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JAC Advance Access published online on September 19, 2005
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dki319
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© The Author 2005. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
Received March 25, 2005
Revised July 14, 2005
Accepted August 7, 2005

Brief report

Identification of a new antitubercular drug candidate, SQ109, from a combinatorial library of 1,2-ethylenediamines

Marina Protopopova 1*, Colleen Hanrahan 1, Boris Nikonenko 1, Rowena Samala 1, Ping Chen 1, Jackie Gearhart 1, Leo Einck 1, and Carol A. Nacy 1

1 Sequella, Inc., 9610 Medical Center Drive, Suite 200, Rockville, MD 20850, USA

* To whom correspondence should be addressed.
Marina Protopopova, E-mail: marinaprotopopova{at}sequella.com


  Abstract

Objectives: The aim of this study was to identify a candidate drug for clinical development from a previously synthesized combinatorial library based on the 1,2-ethylenediamine structure of ethambutol.

Methods: Sixty-nine of the most potent hits against Mycobacterium tuberculosis from the original studies were subjected to a sequential set of tests in vitro and in vivo--determination of MIC for M. tuberculosis H37Rv, cytotoxicity, intracellular antimycobacterial activity, permeability evaluation and in vivo efficacy testing.

Results: Twenty-seven compounds with MICs of ≤15.6 µM were tested on Vero cells to determine in vitro cytotoxicity (IC50) and to establish a selectivity index (SI) (SI = IC50/MIC). Ten compounds with acceptable SI were tested for activity against intracellular bacteria--all were equivalent (within 1%) or superior to ethambutol and several demonstrated cidal activity. Five of the most potent compounds were tested for in vivo efficacy in a murine model of chronic tuberculosis infection.

Conclusion: Compound SQ109 with an MIC of 0.7-1.56 µM (H37Rv, Erdman and drug-resistant strains of M. tuberculosis), an SI of 16.7 and 99% inhibition activity against intracellular bacteria, demonstrated potency in vivo and limited toxicity in vitro and in vivo, and was selected for further development.

Keywords: tuberculosis; drugs; in vivo efficacy; cytotoxicity.
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