DIFUNTORUM SR, JOHNSON K, GROSS M, GARCIA M, TANAKA R, HOCH U, RAMANATHAN-GIRISH S, KAIZERMAN J, DUAN J, BURLI R, MOSER H, LOFLAND D; Interscience Conference on Antimicrobial Agents and Chemotherapy (43rd: 2003: Chicago, Ill.).

Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 2003 Sep 14-17; 43: abstract no. F-2148.

Genesoft Pharmaceuticals, South San Francisco, CA.

BACKGROUND: GSQ 7302 is representative of the SMAT class of compounds that exhibit antibacterial, antiviral, and antiprotozoal activity. This unique spectrum of activity is thought to result from binding to AT-rich sequences in the minor groove of DNA. The current studies focus upon the in vitro and in vivo oral activity against Streptococcus pneumoniae (SP). METHODS: GSQ 7302 MICs were determined using a NCCLS broth microdilution assay against a panel of 10 ATCC strains of SP. In vitro bactericidal activity of GSQ 7302 was assessed by time-kill studies and the post antibiotic effect (PAE) by a 1 hr exposure of 10x GSQ 7302. IV and oral pharmacokinetics at 10 mg/kg were determined in mice with quantitation of plasma levels by LC/MS/MS. Oral efficacy of GSQ 7302 was assessed in a mouse model of lethal SP infection. RESULTS: The MIC[90] and MIC[50] (mcg/ml) of GSQ 7302 against 10 drug-sensitive and resistant SP strains were 0.5 mcg/ml. The average of two time-kill studies showed a 3 log[10] reduction at 10x the MIC against SP 49619 after 24 hours. The PAE of SP 49619 was about 2 hours. Pharmacokinetic analysis of GSQ 7302 revealed low clearance, high volume of distribution, an elimination half-life of 2-4 hr, and 35% oral bioavailability. Moreover, GSQ 7302 exhibited significant oral efficacy with administraion post-infection in the lethal lung infection mouse model. Once daily dosing at 100 mg/kg for 3 days yielded 100% long-term protection. CONCLUSIONS: GSQ 7302 displays good in vitro antibacterial activity against SP. Furthermore, GSQ 7302 is a unique SMAT in that it exhibits robust oral efficacy in a mouse lethal lung infection model. Mechanistic studies indicated bactericidal antibacterial activity with a modest PAE.

Publication Types:

• Meeting Abstracts

Keywords:

• Animals
• Anti-Bacterial Agents
• In Vitro
• Mice
• Microbial Sensitivity Tests
• Pneumococcal Vaccines
• Streptococcus pneumoniae

Other ID:

• GWAIDS0026123

UI: 102265747

From Meeting Abstracts