ABSTRACT
The majority of antibiotics in clinical use or in clinical trials are secondary metabolites of microorganisms or semisynthetic derivatives of secondary metabolites (Strohl, 1997). They range in size from the relatively small ß-lactams (penicillins and cephalosporins) which are composed primarily of cyclized tripeptides, to the more complex heptapeptide glycopeptides, the 14-and 16membered macrolides, and the 13-amino acid cyclic lipopeptide daptomycin. Most of these molecules are too complex to synthesize chemically by economically feasible processes. Their complexity also precludes synthesizing them de novo by traditional or combinatorial chemistry. Indeed, a recent survey of natural product and synthetic compound databases indicated that 40% of natural products are not represented in synthetic compound databases (Henkel et al., 1999). It is unlikely that combinatorial chemistry will ever match the complexity of microbial biosynthesis, which employs highly sophisticated enzymes, such as giant multi-domain polyketide synthases (PKSs), nonribosomal peptide synthetases (NRPSs), a multitude of glycosyltransferases that utilize diverse deoxysugars, and many other tailoring enzymes such as hydroxylases, haloperoxidases, acylases and methyltransferases. It is the goal of molecular
genetic and combinatorial biology approaches to harness and further direct the evolution of complex biosynthetic pathways to expand the repertoire of secondary metabolites, such as antibiotics.
