Discovery and development of new 3-lactam antibiotics

The discovery of the various classes of 8-lactam antibiotics is reviewed and the derived structures with clinical potential highlighted. In addition, the involvement of carbapenam intermediates in the biosynthesis of carbapenems is discussed. Novel non-8-lactam compounds detected via bioassays for -lactams are listed. It is well over 50 years since the discovery of penicillin; it is over 40 years since the recognition of its chemotherapeutic potential by the Florey School at Oxford in the early 1940's. Since the end of World War II commercial and academic interest and investment in 3—lactam antibiotics has been high and has led to a wide array of antibacterial agents of immense chemotherapeutic value to man. I would like to review some of the approaches used over the years to discover new 13—lactam antibiotics and show how such compounds have resulted in new agents being made available to the clinician in order to combat bacterial infection. In general the discovery of new 3—lactams from natural sources has prompted a complementary explosion in synthetic organic chemistry to provide analogous structures. With only a few exceptions it is not unreasonable to say that the detection and characterisation of new 13—lactams from microorganisms has been the major source of inspiration for the design of new r3—lactams with potential chemotherapeutic value. The initial discovery of penicillin, while perhaps considered to be an excellent example of serendipity, has been rationalised (ref. 1). An agar plate inoculated with a Staphylococcus sp. became contaminated with a strain of Penicillum notatum. The plate was laid aside at room temperature; the P.notatum grew, and when the plate was eventually incubated, the growth of the Staphylococcus was affected because of the antibacterial substance (penicillin) which had diffused into the agar and so a typical zone of inhibition in the vicinity of the mould was obtained. Thus we have a screening organism (a Staphylococcus strain) and a random isolate (P.notatum) yielding a novel antibiotic substance, predominantly penicillin F, ! The reinvestigation, development and large scale production studies by Florey and his colleagues in Oxford and their wartime collaboration with American associates and industrialists led to the large scale manufacture of penicillin G, 2 using P.chrysogenun. Other penicillin derivatives could be prepared by feeding certain precursors to the fermentation. The detailed investigations of the discrepancy between bioassays and chemical assays resulted in Beecham scientists in the mid 1950's recognising 6—aminopenicillanic acid (6—APA), 3, as a precursor of penicillins during the fermentation of P.chrysogenum. These results prompted the preparation of 6—APA on a large scale, principally by the enzymatic deacylation of penicillin G. Chemical reacylation of 6—APA then led to the preparation and evaluation of many thousands of new penicillins by numerous pharmaceutical companies and the clinical use of compounds such as methicillin, ampicillin, amoxycillin, carbenicillin, ticarcillin, azlocillin, mezlocillin, piperacillin, mecillinam and flucloxacillin (ref. 2). Previous to the discovery of 6—APA, studies at Oxford had uncovered the cephalosporin family of 3—lactams following detailed examination of the antibacterial substances isolated from a strain of Cephalosporium acremonium supplied by Professor Brotzu. Brotzu had suggested that from microorganisms associated with sewage outflows one could expect to obtain compounds antagonistic to sewage bacteria. C.acremonium was such an organism and Abraham and his colleagues, in addition to finding penicillin N, 4, isolated cephalosporin C, 5 (ref. 3). It is worth remembering that this culture also gave the steroids of the cephalosporin P series, the first members of the fusidic acid class of antibiotics (ref. 4). Development of this discovery of cephalosporin C led to the clinical use of cephalothin, cephaloridine, cephalexin etc. — the so called first generation cephalosporins (ref. 5). 475