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A number of C-2 aminoalkenylthio-carbapenem derivatives possessing both the (5R,6R, 8S)- and the (5R,6S,8R)-stereochemistries have been prepared from the olivanic acids MM 22382 and MM 22383, respectively. Certain members of this new class of compounds displayed potent, broad spectrum antibacterial activity as well as improved stability to human kidney homogenate.

Michael addition of thiols to 6-substituted azabicyclo[3.2.0]hept-2-ene-2-carboxylates, followed by reintroduction of the double bond with iodobenzene dichloride–pyridine under anhydrous conditions, provides a biomimetic strategy for the synthesis of 3-alkylthio-substituted olivanic acids (carbapenems) and their derivatives. This is illustrated by syntheses of representatives of the PS-5 and MM22381 series of antibacterial natural products.

Samples of three sulphated olivanic acids were prepared from a culture of Streptomyces olivaceous. The side chains at C3 were -S-CH=CH.NHCOCH (MM13902);-S(0)CH=CH.NHC0CH3 (MM4550) and -S.CH2 CH2 NHCOCH3 (MM17880). A mixture of the three metabolites was partially resolved by HPLC using a reversed-phase C18 silica column. The separation was improved by incorporating in the mobile phase tetra-alky1ammonium compounds as ion-pairing reagents. By these means MM13902 was separated from the others. Improved separations of MM4550 and MM17880 were achieved using β-cyclodextrins covalently bound onto silica columns. The more flexible side chain of MM17880 was more able than that of MM4550 to fit into the truncated β-cyclodextrin cone.

The application of inhibitors to block the beta-lactamase destruction of penicillins and cephalosporins by resistant bacteria is a potentially useful way of improving the efficacy of established compounds. Certain semi-synthetic penicillins and cephalosporins have been found to be competitive inhibitors of selected beta-lactamases but an examination of streptomycete culture fluids has revealed two new types of beta-lactam compound: clavulanic acid, which is a progressive inactivator of a wide range of beta-lactamases, and the olivanic acids, which are both broad-spectrum antibiotics and potent beta-lactamase inhibitors. Penicillanic acid sulphone and 6-beta-bromopenicillanic acid have been shown to be significant inhibitors of beta-lactamase. The chemotherapeutic application of these compounds is discussed.

The 1,3-dipolar cycloaddition of activated acetylenes to 6-(1-azidoethyl) olivanic acid derivatives afforded the corresponding 6-[1-(1,2,3-triazol-1-yl)ethyl] compounds.

4-Allylazetidin-2-one, prepared from penta-1,4-diene and chlorosulphonyl isocyanate, has been used to synthesise the parent 7-oxo-1-azabicyclo[3.2.0] hept-2-ene-2-carboxylate system of the naturally occurring olivanic acids, using an intramolecular Witting reaction to construct the 2,3-double bond. Cyclisation of ketones derived from the 4-allyl grouping produced 3-substituted derivatives, while use of the azetidin-2-one prepared from hexa-1,5-diene and chlorosulphonyl isocyanate has given the homologous 8-oxo-1-azabicyclo[4.2.0]oct-2-ene system.

In summary, Table XVI shows the inhibition profiles of representative beta-lactamases from each major class of Richmond and Sykes. Either resistance (R) or sensitivity (S) is given as a general guide to the type of compounds likely to inhibit each class. Thus the (qualitative) statements regarding the effectiveness of clavulanic acid can be taken to represent those for the penam sulfones and similarly for MM4550 and the other olivanic acids, carpetimycins, PS series, and asparenomycins. This can also be said of cloxacillin and the other aromatic carboxamido penicillins. Compounds are also included which are specifically or particularly inhibitory to certain beta-lactamases.

(±)-(3R*,4R*)-4-(2,2-Dimethoxyethyl)-3[(1S*)-1-hydroxyethyl]azetidin-2-one (7), which has been stereoselectively synthesised via the 4-methoxycarbonylisoxazoline (4), was converted into (±)-epithienamycins A (2) and B (3)[(±)-olivanic acids MM22380 and MM22382], (±)-deacetylepithienamycin A (20), and the 2-phenylthio-substituted compound (19). This total synthesis confirms the relative stereochemistry of the natural antibiotics.

Streptomyces olivaceus ATCC 31365 produces a family of novel beta-lactam antibiotics collectively referred to as the olivanic acids. Seven such compounds, MM 4550, MM 13902, MM 17880, MM 22380, MM 22381, MM 22382 and MM 22383 have been identified which have the same carbapenem nucleus but with different side chains attached to the nucleus. The compounds with an (8S) hydroxyethyl substituent and cis-orientated beta-lactam protons, MM 22380 and MM 22382, and their sulphate esters, MM 17880 and MM 123902, are potent antibiotic with MIC values against Gram-positive and Gram-negative bacteria in the range 0.1 3.1 microgram/ml. The corresponding (8S) hydroxyethyl compounds with trans-beta-lactam protons, MM 22381 and MM 22383, also have broad-spectrum activity but are rather less potent than the cis-compound. In addition to their antibiotic activity, the olivanic acids inhibit a number of beta-lactamases and enhance the activity of beta-lactams such as amoxycillin against beta-lactamase-producing bacteria. Significant differences are observed both in antibacterial activities and in beta-lactamase inhibition properties when the olivanic acids are compared with the related thienamycin antibiotics which have (8R) rather than (8S) stereochemistry and trans-beta-lactam protons.

The olivanic acids MM 4550, MM 13902 and MM 17880 are members of a new family of beta-lactam antibiotics. An isolation and purification process utilising ion-par extraction and ion-exchange chromatography is described and the metabolites are characterised by physico-chemical and biological properties.

The trans- and cis-substituted β-lactam isomers of p-nitrobenzyl 3-(2-acetamidoethylthio)-6-ethyl-7-oxo-1-azabicyclo[3.2.0]heptane-2-carboxylate can be oxidised with iodobenzene dichloride–pyridine under anhydrous conditions to give the 3,4-unsaturated esters, which after isomerisation and deprotection afford the sodium salts of (±)-PS-5 and (±)-6-epi PS-5.

From chemical and kinetic studies of the interaction of the RTEM beta-lactamase from Escherichia coli with three derivatives of olivanic acid, MM22382 (1), MM13902 (2), and MM4550 (3), a mechanism for the inhibition of the enzyme by these compounds is proposed: the interaction proceeds by formation of an acyl-enzyme, the delta 2-pyrroline, which may either deacylate or undergo tautomerization to the more tightly bound delta 1-pyrroline. The ability of olivanic acids to inhibit the enzyme thus depends on the partitioning of the acyl-enzyme to the delta 1-pyrroline ( a process that competes with the normal hydrolytic pathway) and on the rate of regeneration of free enzyme from this complex.

The 3-(E)-2-acetamidoethenylthio-substituent of olivanic acid derivatives reacts with hypobromous acid to afford a C-3 thiol which undergoes alkylation reactions and addition to propiolates.

Publisher Summary Studies have clarified the confusion between the terms prodrug and soft drug. These terms represent opposite concepts: a prodrug is inactive by design and it is activated predictably in vivo , while soft drugs are active species designed to undergo a predictable and controllable metabolic deactivation. Simple prodrug design cannot solve the variety of transport-delivery problems, particularly when site-specific or site-enhanced delivery is the objective. Chemical delivery systems (CDS) have been proposed as an approach to this problem. This chapter explains a broader view of this subject, concentrating on the recent developments. Improvement of the pharmacodynamic properties of anti-bacterial agents via transient chemical modification continues to be an area of active interest. The design of prodrugs of β-lactam antibiotics has recently been reviewed. The relationship between the physical–chemical properties and oral bioavailability in mice of prodrugs of parenteral cephalosporins is studied to obtain the fundamental information for the rational design of oral prodrugs. Bacmecillinam is a new orally well-absorbed prodrug of the amidinopenicillin mecillinam. Acyloxyallyl esters of ampicillin are investigated as novel ester prodrugs. Mutual prodrugs of the olivanic acids have been investigated with the preparation of the double ester formaldehyde hydrate prodrugs.

7-(1-Hydroxyethyl)-8-oxo-3-oxa-1-azabicyclo[4.2.0]octanespiro-2-cyclohexane has been elaborated to provide appropriately substituted thioester-phosphoranes; these have been cyclised via an intramolecular Wittig reaction and the products deprotected to furnish (±)-MM-22383 and (±)-N-acetyldehydrothienamycin.

7-(1-Hydroxyethyl)-8-oxo-3-oxa-1-azabicyclo[4.2.0]octanespiro-2-cyclohexane has been elaborated to provide appropriately substituted thioester-phosphoranes; these have been cyclised via an intramolecular Wittig reaction and the products deprotected to furnish (±)-MM-22383 and (±)-N-acetyldehydrothienamycin.

The trans- and cis-substituted β-lactam isomers of p-nitrobenzyl 3-(2-acetamidoethylthio)-6-ethyl-7-oxo-1-azabicyclo[3.2.0]heptane-2-carboxylate can be oxidised with iodobenzene dichloride–pyridine under anhydrous conditions to give the 3,4-unsaturated esters, which after isomerisation and deprotection afford the sodium salts of (±)-PS-5 and (±)-6-epi PS-5.

The syntheses of PS-5 (1) and analogues from the olivanic acids MM 17880 (4) and MM 13902 (10), including the use of a new carboxy protecting group, the p-methoxycarbonylbenzyl group, are reported together with the chemical elucidation of the stereochemistry at C-8 of the olivanic acids.

The 3-(E)-2-acetamidoethenylthio-substituent of olivanic acid derivatives reacts with hypobromous acid to afford a C-3 thiol which undergoes alkylation reactions and addition to propiolates.