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Antimicrobial Agents and Chemotherapy, October 2002, p. 3168-3174, Vol. 46, No. 10
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.10.3168-3174.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

In Vitro Antimicrobial Activity of GSQ1530, a New Heteroaromatic Polycyclic Compound

Yigong Ge,^1* Stacey Difuntorum,¹ Sofia Touami,¹ Ian Critchley,² Roland Bürli,¹ Vernon Jiang,¹ Ken Drazan,¹ and Heinz Moser¹

Genesoft Inc., South San Francisco, California,¹ Focus Technologies, Herndon, Virginia²

Received 19 March 2002/ Returned for modification 10 May 2002/ Accepted 24 June 2002

GSQ1530 is a compound derived from a newly identified class of antibiotics referred to as heteroaromatic polycyclic (HARP) antibiotics. The aim of this study was to assess the in vitro antimicrobial activity of GSQ1530. By using an NCCLS broth microdilution assay, the activities of GSQ1530 and other antibiotics were coevaluated against 215 clinical isolates. The MICs at which 90% of isolates are inhibited (MIC₉₀s) of GSQ1530 for methicillin-susceptible Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) were 2 and 4 µg/ml, respectively. The MIC₉₀s of GSQ1530 for the streptococci tested were 2 µg/ml or less, regardless of their susceptibilities to other antibiotics. The MIC₉₀ of GSQ1530 for the enterococci tested (including vancomycin-resistant enterococci) was 4 µg/ml. No cross-resistance was found between GSQ1530 and other known antibiotics. In a separate assay, GSQ1530 demonstrated excellent activity against vancomycin-intermediate-susceptible staphylococci (MIC₉₀, 1 µg/ml). The minimal bactericidal concentration test was conducted with 73 clinical isolates; GSQ1530 was cidal against streptococci and staphylococci but static against enterococci. An in vitro killing kinetic study revealed a time-dependent profile, with at least a 3-log reduction of bacterial growth within 6 h after exposure to four times the MICs of GSQ1530 for both S. aureus and Streptococcus pneumoniae. The checkerboard study showed that GSQ1530 had a synergistic interaction with rifampin against MRSA. The test medium was found to have little effect on in vitro antimicrobial potency. The MICs of GSQ1530 for gram-positive cocci were 4- to 32-fold higher in the presence of serum proteins. GSQ1530 has high levels of plasma protein binding (91 and 89% for rat and human plasma, respectively). These preliminary results demonstrate that GSQ1530, a representative compound of our novel HARP antibiotics, has broad-spectrum activity against gram-positive bacteria. This novel class of antibacterial compounds is profiled in vivo to assess the therapeutic potential in humans. Ongoing in vivo studies will assess whether this class of molecules has promising in vivo efficacy and safety profiles.

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* Corresponding author. Mailing address: Genesoft Inc., 7300 Shoreline Ct., South San Francisco, CA 94080. Phone (650) 837-1826. Fax (650) 827-0475. E-mail: jge{at}genesoft.com.

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Antimicrobial Agents and Chemotherapy, October 2002, p. 3168-3174, Vol. 46, No. 10
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.10.3168-3174.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

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