Izumenolide

Enzyme inhibitors selected from either natural product screening or synthetic chemistry programmes can be characterized according to a number of criteria to determine their usefulness as potential drug candidates. Inhibition may be classified as either irreversible or reversible. Irreversible inhibitors may be described with respect to first order rate constants or half-times for inactivation. Reversible inhibitors should be evaluated with respect to Ki values rather than I50 values. Assays should be designed using the simplest and most precise procedures available. If possible, assays utilizing continuously-recording methods should be selected. When reversible inhibitors are desired, greater sensitivity for inhibition is achieved using low substrate concentrations. For irreversible inhibitors or tight-binding competitive inhibitors, low enzyme concentrations also result in greater inhibitory sensitivity. The order of addition of enzyme and substrate should be varied to determine whether inhibition requires preincubation of enzyme and inhibitor for maximum effect. Time-dependence of inhibition should also be established. Enzyme inhibitors should be specific for the enzyme that is being targeted. Novel competitive inhibitors of angiotensin-converting enzyme were isolated in the author's laboratory using the above philosophy of screening for enzyme inhibitors. The properties of the muraceins, phenacein and aspergillomarasmine A' are discussed.

Inhibition of a beta-lactamase of Streptomyces cacaoi by CP-45,899, izumenolide and cephamycins was investigated and compared with that of a beta-lactamase of Bacillus cereus. S. cacaoi enzyme could not hydrolyze CP-45,899. Instead, hydrolysis of benzylpenicillin by the enzyme was inhibited in the presence of CP-45,899. Although inhibition increased gradually with time, the inhibition line produced by CP-45,899 with time less curved than that produced by clavulanic acid and PS-5. Furthermore, preincubation of S. cacaoi beta-lactamase with CP-45,899 for up to 120 seconds did not obviously affect the degree of inhibition. When the concentration was lowered, it behaved as a competitive inhibitor, a Ki value being 6.2 X 10(-7) M. Izumenolide, on the other hand, did not inhibit the enzyme activity of S. cacaoi beta-lactamase at 1.28 X 10(-4) M, although it inhibited B. cereus enzyme slightly in a competitive manner. Oganomycins were inert to the both beta-lactamases.U

M-GTFI, an inhibitor of glucosyltransferase from S. mutans was produced by Micromonospora narashinoensis strain No. 731. The isolation procedure for M-GTFI was improved and established for spectroscopic analyses, and some properties of the inhibitor were investigated. The structure of M-GTFI was shown to be trisodium [2-sulphonato-(E)-9-undecenyll-oxacyclotriacont-(E)-3- en-2-one, 16, 18-bis sulphonate. The chemical structure of M-GTFI was therefore similar to that of izumenolide which is a beta-lactamase inhibitor containing sulfate ester groups in its molecule. The inhibitory characteristics of M-GTFI were parallel to that of other inhibitory compounds containing sulphate esters but the spectrum of activity was wider.