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Antimicrobial Agents and Chemotherapy, November 2003, p. 3448-3457, Vol. 47, No. 11
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.11.3448-3457.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Pharmacology of Novel Heteroaromatic Polycycle Antibacterials

M. Gross,¹ R. Bürli,² P. Jones,² M. Garcia,¹ B. Batiste,¹ J. Kaizerman,² H. Moser,² V. Jiang,² U. Hoch,¹ J.-X. Duan,² R. Tanaka,¹ and K. W. Johnson^1*

Pharmacology,¹ Chemistry Departments, GeneSoft Pharmaceuticals, South San Francisco, California 94080²

Received 22 January 2003/ Returned for modification 9 June 2003/ Accepted 17 July 2003

Heteroaromatic polycycle (HARP) compounds are a novel class of small (M_w, 600 to 650) DNA-binding antibacterials. HARP compounds exhibit a novel mechanism of action by preferentially binding to AT-rich sites commonly found in bacterial promoters and replication origins. Noncovalent binding in the minor groove of DNA results in inhibition of DNA replication and DNA-dependent RNA transcription and subsequent bacterial growth. HARP compounds have previously been shown to have potent in vitro activities against a broad spectrum of gram-positive organisms. The present report describes the extensive profiling of the in vitro and in vivo pharmacology of HARP antibacterials. The efficacies of representative compounds (GSQ-2287, GSQ-10547, and GSQ-11203), which exhibited good MIC activity, were tested in murine lethal peritonitis and neutropenic thigh infection models following intravenous (i.v.) administration. All compounds were efficacious in vivo, with potencies generally correlating with MICs. GSQ-10547 was the most potent compound in vitro and in vivo, with a 50% effective dose in the murine lethal peritonitis model of 7 mg/kg of body weight against methicillin-sensitive Staphylococcus aureus (MSSA) and 13 mg/kg against methicillin-resistant S. aureus (MRSA). In the neutropenic mouse thigh infection model, GSQ-11203 reduced the bacterial load (MRSA and MSSA) 2 log units following administration of a 25-mg/kg i.v. dose. In a murine lung infection model, treatment with GSQ-10547 at a dose of 50 mg/kg resulted in 100% survival. In addition to determination of efficacy in animals, the pharmacokinetic and tissue disposition profiles in animals following administration of an i.v. dose were determined. The compounds were advanced into broad safety screening studies, including screening for safety pharmacology, genotoxicity, and rodent toxicity. The results support further development of this novel class of antibiotics.

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* Corresponding author. Mailing address: Department of Pharmacology, GeneSoft Pharmaceuticals, 7300 Shoreline Ct., South San Francisco, CA 94080. Phone: (650) 837-1864. Fax: (650) 827-0479. E-mail: kjohnson{at}genesoft.com.

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Antimicrobial Agents and Chemotherapy, November 2003, p. 3448-3457, Vol. 47, No. 11
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.11.3448-3457.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

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