The continuing specter of resistance to antimicrobial agents has driven a sustained search for new agents that possess activity on drug resistant bacteria. Although several paths are available to reach this goal, the most generalized would be the discovery and clinical development of an agent that acts on a new target which has not yet experienced selective pre-ssure in the clinical setting. Such a target should be essential to the growth and survival of bacteria, and sufficiently different from, or better still non-existent in, the human host. The transglycosylation reaction that polymerizes biochemical intermediates into peptidoglycan qualifies as such a target. This biochemical system accepts the basic unit N-acetylglucosamine-b-1,4- N-acetyl-muramyl-pentapeptide-pyrophosphoryl-undecaprenol (lipid II), and leads to polymerization of the N-acetylglucosamine -b-1,4-N-acetyl-muramyl-pentapeptide segment into peptidoglycan. Approaches to targeting this reaction include modification of known glycolipid and glycopeptide natural product antibiotics. The synthesis and antibacterial activity of synthetic analogs of moenomycin having novel antibacterial activities not present in the parent structure will be presented, together with the combinatorial chemistry and assay systems leading to their discovery. Likewise, we will discuss chemical modifications to specific glycopeptide antibiotics that have extended their spectrum to include vancomycin resistant enterococci that substitute D-alanyl-D-lactate for D-alanyl-D-alanine in their peptidoglycan. Two differing theories, one positing the generation of high affinity, specific binding to D-alanyl-D-lactate via glycopeptide dimerization and/or membrane anchoring, and the other supporting direct targeting of the modified glycopeptide to the transglycosylation complex, seek to explain the mechanism of action on vancomycin resistant enterococci. Biochemical evidence in support of these two theories will be discussed.
Keywords: inhibition, transglycosylation, bacterial peptidoglycan synthesis, N actylgulucosamine 1 4 N acetyl muramyl pantapeptide pyrophosphoryl undecaprenol, N acetylgucosamine, vancomycin resistant enterococci, peptidoglycan, D alanyl D lactate via glycopeptide, VISA vancomycin intermediate staphyloccus auresu GISA glycopeptide, strepoccous pneumoniae, penicillin binding protein, moenomycin disaccharide analogs, combinatorial chemistry, antibacterial activity, natural products inhibitors, mersacidin, novel glycopeptide analogs, eremomycin, chioroemeomycin, teicoplanin, chiorobiphenyl disaccharide, chiorbiphenyl desleucyl vancomycin, GicNAc MurNAc pentapeptide pyrophosphoryl undecaprenol
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Published on: 01 March, 2012
Page: [801 - 820]