F1-369. Broad Spectrum Antibacterial Activity of Novel Compounds with Activity against Vancomycin- and Methicillin-Resistant Strains
Session: Poster Session: New Glyco- and Lipopeptides
Saturday, October 25, 2008: 12:00 AM
Room: Hall C
Background: Vancomycin is a glycopeptide that binds to the terminal D-Ala-D-Ala dipeptide of peptidoglycan precursors, abrogating cell wall synthesis. Resistance to vancomycin is a recognised clinically significant problem, resulting from substitution of D-lactic acid for the terminal D-Ala, with loss of affinity for vancomycin. A series of compounds were designed to bind to both D-Ala-D-Ala and D-Ala-D-Lac terminal ends of the peptidoglycan precursor as potential antibacterials. Methods: Compounds were synthesised and tested for antibacterial activity in vitro using the microbroth dilution method against strains including staphylococci, enterococci, streptococci, methicillin-resistant staphylococci (MRSA), vancomycin-intermediate (VISA), vancomycin-resistant (VRSA) staphylococci and linezolid-resistant staphylococci. In vivo antibacterial activity was assessed in the mouse nasal decolonisation model. Results: AVX13616 and other compounds showed broad spectrum antibacterial activity against a range of isolates with MICs of 2-4 μg/mL against S. aureus, coagulase negative staphylococci, enterococci, MRSA, VISA and VRSA. A single application of 5% (w/w) AVX13616 (approximately equimolar to 2% mupirocin) was as effective as 2% mupirocin administered twice a day for 5 days in nasal decolonisation of MRSA in mice. Conclusions: A series of compounds were synthesised with antibacterial activity against a range of gram positive organisms, including organisms resistant to vancomycin, linezolid and methicillin. The compounds were designed to retain binding activity against a D-Ala-D-Lac terminal peptide, where vancomycin binding is reduced. The lead compound AVX13616 was as active as mupirocin in a nasal decolonisation model but required only a single application. The compounds are being developed for topical indications and/or wound infection/catheter-related infections.
Andrea McCracken1, David Rhodes2, John Deadman2, John Bremner3, Jonathan Coates2, Paul Keller, PhD4, Steven Pyne3 and  A. McCracken, None., (1)Avexa Ltd, Melbourne, Australia, (2)Avexa Ltd, (3)University of Wollongong, (4)Merck & Co., Inc., North Wales, PA


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