The total world market for b-lactam antibiotics is now
estimated to be ~US$ (hereafter $) 15 billion with
cephalosporin dosage form sales at ~$9.9 billion and
penicillin dosage form sales at ~$5 billion (Barber 1996,
2000). In 1996, the total world antibiotic market at the
dosage form level was estimated to be ~$23 billion
(Demain and Elander 1999). The United States antibacterial market was >$8 billion with cephalosporins
($3.6 billion), penicillins ($1.2 billion), fluoroquinolones
($0.9 billion), tetracyclines ($0.5 billion) and macrolides
($0.4 billion) reported recently by Strohl (1999). In
contrast, the total world sales for antifungal products was
~$3 billion and growing and the antiviral market was
~$2.6 billion with a market forecast of >$5 billion for
2000. The b-lactam antibiotics now account for over 65%
of the world antibiotic market. There are now more than
50 marketed cephalosporins. Many of these are listed in
Table 1.
The biosynthetic pathways for the penicillins, cephalosporins and cephamycins are well characterized both
genetically and biochemically (Demain et al. 1998). A
generalized pathway is shown in Fig. 1. Most of the
important genes have now been cloned, with the exception of the isopenicillin N epimerase (cef D) gene
(Brakhage 1998). Amplification of certain of the genes,
in particular the deacetoxycephalosporin C synthase (cef
E) gene, has been reported to increase cephalosporin C
production and to decrease the levels of deacetoxycephalosporin C (DAOC) in production fermentation
broths (Skatrud et al.1989; Basch and Chiang 1998). The
transfer to and expression of the cef E gene from
Streptomyces clavuligerus in Penicillium chrysogenum
resulted in the formation of adipyl-7-aminodeacetoxycephalosporanic acid (adipyl-7-ADCA) when the altered
P. chrysogenum strain was fed adipic acid (Crawford et
al. 1995). In this manner, the inherent greater biosynthetic
capacity of P. chrysogenum may be used to produce
DAOCs, molecules—with expanding markets—that are
far more expensive to manufacture than penicillins