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JAC Advance Access originally published online on September 19, 2005
Journal of Antimicrobial Chemotherapy 2005 56(5):968-974; 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

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

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

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

Received 25 March 2005; returned 14 May 2005; revised 14 July 2005; accepted 7 August 2005

* Corresponding author. Tel: +1-301-217-3832; Fax: +1-301-762-7778; E-mail: marinaprotopopova{at}sequella.com

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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