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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.

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.

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.

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.