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.
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