MM-17880

Based on the working hypothesis that the OA-6129 group of carbapenem compounds might be the direct precursors for PS-5, epithienamycins A and C and MM 17880, Streptomyces fulvoviridis A933 17M9, a producer of PS-5, PS-6, PS-7, PS-8, epithienamycins A, B, C and D, MM 17880, MM 13902 and MM 4550, was subjected to NTG-mutation to provide a blocked mutant numbered 1501 which was found to produce OA-6129 A, OA-6129B1, OA-6129B2 and OA-6129C instead of PS-5, epithienamycins A and C and MM 17880, respectively. In a cell-free system, the parent strain demonstrated an ability to convert OA-6129A to NS-5, whereas the mutant did not. The L- and D-amino acid acylases were also shown to depantothenylate the OA-6129 group of carbapenems.

The production of beta-lactamase is the most important mechanism of bacterial resistance to beta-lactam antibiotics. Attempts to find an inhibitor of beta-lactamase were made as early as the 1940s and 1950s but without success. In the early 1950s, it was found that certain semisynthetic penicillins could function as beta-lactamase inhibitors, but none found a clinical place in this capacity. A program of screening microorganisms for the production of naturally occurring inhibitors was begun in 1967. This process led to the discovery of the olivanic acids and clavulanic acid. Clavulanic acid, formulated with amoxicillin and later with ticarcillin, became available for clinical use in 1981. Since the introduction of clavulanic acid, other beta-lactamase inhibitors have been developed, including sulbactam and tazobactam. It remains to be seen whether these will have any advantage over clavulanate for clinical use.

A specific acylase designated A933 acylase was isolated and purified to 90% protein homogeneity from Streptomyces fulvoviridis A933 17M9 which produces PS-5, epithienamycins A and C and MM 17880 together with minor carbapenem analogs, penicillin N and cephamycin C. This enzyme was found to catalyze the depantothenylation of OA-6129 carbapenems; the acyl exchange of OA-6129 carbapenems with acyl CoA's; the deacetylation of N-acetyl-L-amino acids; and the acylation of NS-5 and 6-aminopenicillanate with acyl CoA's, whereas the deacetylation of PS-5 and N-acetyl-D-amino acids; and the deacylation of benzylpenicillin and cephalosporin C were not observed. Similar enzyme activities were also detected in Streptomyces cattleya, Streptomyces cremeus subsp. auratilis and Streptomyces argenteolus which are all carbapenem producers.