Department of Chemistry, University of Cambridge
It is over a decade ago that the structures of the glycopeptide (vancomycin group) antibiotics, and the molecular basis by which they bind cell wall precursors terminating in -L-Lys-D-Ala-D-Ala, were established.1 However, we have recently shown that these antibiotics dimerise to varying degrees, and implied dimerisation in their mode of action.2-5 An antibiotic which shows no measurable propensity to dimerise, teicoplanin, may locate itself at the site where it interferes with the process of cell wall biosynthesis by use of a membrane anchor.4,5
Pathogenic bacteria which are resistant to vancomycin produce the modified cell-wall precursor terminating in -L-Lys-D-Ala-D-Lac. At Eli Lilly & Co., a strongly dimerising glycopeptide has been modified by the addition of a lipophilic sidechain.6 This compound is now active against the abovementioned pathogens. Factors which may be relevant to this activity will be discussed.
References
1. Williams, D.H. (1989) Accts. Chem. Res. 17, 364.
2. Waltho, J.P. & and Williams, D.H. (1989) J. Amer. Chem. Soc. 111, 2475.
3. Mackay, J.P., Gerhard, U., Beauregard, D.A., Maplestone, R.A., & Williams, D.H. (1994) J. Amer. Chem. Soc. 116, 4581-4590.
4. Gerhard, U., Mackay, J.P., Maplestone, R.A., & Williams, D.H. (1993) J. Amer. Chem. Soc., 115, 232-237.
5. Beauregard, D.A., Williams, D.H., Gwynn, M.N., & Knowles, D.J.C. (1995) Antimicrob. Agents Chemotherapy 39, 781-785.
6. See, for example, European Patent Application 90313410.4, publication no. 0 435 503 A1.