Mark S.Butler and David J.Newman between various bacteria.The advent of the sulfonamides exemplified by Prontosil(5)led to the introduction of synthetic antibacterials with the first clinical efficacy report in 1933 and ultimately leading to the award of the Nobel Prize for Medicine in 1938 to Domagk.This could also be thought of as the first formal prodrug in the antibiotic field as the active principle sulfanilamide(6)is a structural analogue of para-aminobenzoic acid(PABA).PABA competitively inhibits dihydropteroate synthase,thus leading to inhibition of folic acid and bacterial death.So although syn- thesized in the absence of such knowledge,and for an entirely different purpose,it was in retrospect an isostere of a NP. We will briefly discuss the major chemical classes of natural antibiotics and give suitable references to articles which will go into much greater detail for the interested reader in each section. 2.1.1 B-Lactams Following the isolation and identification of penicillin G and then peni- cillin V in the UK and the USA in the early 1940s which was covered in detail in 1998 by Mateles in an excellent reprint entitled History of Penicillin Production [15],the number of penicillin-based molecules that have been produced by semi-and total synthesis to date is well over the 15,000 level. Most of these compounds have started with modification of the fermenta- tion product,6-amino-penicillanic acid(7),which also can be produced by a simple chemical or biochemical deacylation from penicillins.The number above is only indicative as a significant proportion of materials were never published,particularly from industry,as they had marginal or no significant activity over those that had been reported previously. In 1948,the ring-expanded version of penicillin,cephalosporin C,was reported from Cephalosporium sp.by Brotzu and its structure determined in 1961 by the Oxford Group 16,17.As with the penicillin nucleus,this ring expanded molecule also served as the building block(as its 7-amino cephalosporanic acid homologue)for many thousands of cephalosporins, with the first orally-active molecule,cephalexin(8)being introduced in 1970.Since that time,a multitude of cephalosporins have been syn- thesized with the aim of producing molecules that are more resistant to B-lactamases. 6 Mark S. Butler and David J. Newman 6 between various bacteria. The advent of the sulfonamides exemplified by Prontosil® (5) led to the introduction of synthetic antibacterials with the first clinical efficacy report in 1933 and ultimately leading to the award of the Nobel Prize for Medicine in 1938 to Domagk. This could also be thought of as the first formal prodrug in the antibiotic field as the active principle sulfanilamide (6) is a structural analogue of para-aminobenzoic acid (PABA). PABA competitively inhibits dihydropteroate synthase, thus leading to inhibition of folic acid and bacterial death. So although syn￾thesized in the absence of such knowledge, and for an entirely different purpose, it was in retrospect an isostere of a NP. We will briefly discuss the major chemical classes of natural antibiotics and give suitable references to articles which will go into much greater detail for the interested reader in each section. 2.1.1 `-Lactams Following the isolation and identification of penicillin G and then peni￾cillin V in the UK and the USA in the early 1940s which was covered in detail in 1998 by Mateles in an excellent reprint entitled History of Penicillin Production [15], the number of penicillin-based molecules that have been produced by semi- and total synthesis to date is well over the 15,000 level. Most of these compounds have started with modification of the fermenta￾tion product, 6-amino-penicillanic acid (7), which also can be produced by a simple chemical or biochemical deacylation from penicillins. The number above is only indicative as a significant proportion of materials were never published, particularly from industry, as they had marginal or no significant activity over those that had been reported previously. In 1948, the ring-expanded version of penicillin, cephalosporin C, was reported from Cephalosporium sp. by Brotzu and its structure determined in 1961 by the Oxford Group [16, 17]. As with the penicillin nucleus, this ring expanded molecule also served as the building block (as its 7-amino￾cephalosporanic acid homologue) for many thousands of cephalosporins, with the first orally-active molecule, cephalexin (8) being introduced in 1970. Since that time, a multitude of cephalosporins have been syn￾thesized with the aim of producing molecules that are more resistant to `-lactamases