Naturally Occurring Monobactams

WILLIAML. PARKER, JOSEPH O'SULLIVAN, A N D RICHARDB. SYKES

The Squibb lnstitute for Medical Research
Princeton, New Jersey

I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
11. Detection of Monobactains . . . . . . . . . . . . . . . . . . . . 185
111. Individual Monobactams . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186
A. S Q 26,180 . . . . .. 186
B. Sulfiazecin and I zecin . . . . . . . . . . . . . . . . . . . . . . . . . 188
C. EM5400 . . . . . . . . . . . . . . 190
D . SQ 28,332 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192
E. SQ 28,502 and SQ 28,503 . . . . . . . . . . . . . . . . . . . . . . . . . . . 195
IV. Biosynthesis of Monolmctatns . . . . . . . . . . . . . . . . . . . . . . . . . . . 196
V. Bacterially Produced Agents That Synergize with P-Lactains . 200
VI. Conclusions . . . . . .......................... 20 1
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203

I. introduction
For over 40 years, the eukaryotic fungi were the only known producers of
naturally occurring p-lactam antibiotics. By a chance observation in 1928,
Fleming discovered penicillin as a product of the common mold, Penicillium
notatum. From a number of related structures produced by the molds,
benzyl penicillin emerged as the antibiotic compound of choice and became
generally available for the treatment of infectious diseases by the late 1940s.
With the identification and isolation of the penicillin nucleus (6-ami-
nopenicillanic acid) in the late 1950s it was possible for a family of semi-
synthetic penicillins to emerge. The general structure of penicillin along
with the other currently known classes of p-lactam antibiotics is shown in
Fig. 1.
The discovery of cephalosporin C from a species of Cephalosporium
acremonium in 1955 (Newton and Abraham) was the culmination of work
started by Brotzu in 1947. From cephalosporin C, the chemically derived
nucleus (7-aminocephalosporanic acid) opened the way to the development
of the semisynthetic cephalosporins.
By the early 1970s, when these two major classes of clinically useful
antibiotics had been well established, novel p-lactam molecules began to
make their appearance. However, unlike the penicillins and cephalosporins,
these new compounds were not the products of fungi but were secondary
metabolites of the prokaryotic streptomycetes. The first compounds to be
identified were the cephamycins (Nagarajan et al., 1971), similar in structure

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