Olivanic acids, 3-lactamase inhibitors

The sulfated compounds MM 13902 (3, n = (5) and MM 17880 (4) are also broad-spectmm agents, but not as potent as thienamycia and all lack any significant activity against Pseudomonas (73). Many carbapenems are excellent inhibitors of isolated P-lactamases, particularly the olivanic acid sulfoxide MM 4550 (3, n = 1) (3). The possible mechanism of action of the carbapenems as inhibitors of P-lactamases has been discussed in some detail (74). Other carbapenems such as PS-5 (5) (75), the carpetimycins (76), asparenomycins (77), and pluracidomycins (8) are all highly active as antibiotics or P-lactamase inhibitors. The parent nucleus itself (1, X = CH2) is intrinsically active, but chemically unstable (9). 

The olivanic acids (general structure, Fig. 5.5D) are naturally-occurring /3-lactam antibiotics which have, with some difficulty, been isolated from culture fluids of Strep, olivaceus. They are broad-spectrum antibiotics and are potent inhibitors of various types of/3-lactamases. 

The first clinical application of the second strategy (to overcome bacterial resistance by neutralizing the /3-lactamases) was the combination of clav-ulanic acid (5.12) and amoxicillin. The efficacy of clavulanic acid has stimulated research on other inhibitors of /3-lactamases, leading to the discovery of a number of other inactivators such as sulbactam (5.13), 6/3-bromopenic-illanic acid (5.14), and olivanic acid (5.15) [44] [45],... 

Mechanistic investigations have shown that these compounds behave as suicide inhibitors (preferably called mechanism-based inactivators) in the sense that they are recognized by /3-lactamases as substrates, but the great stability of the acyl-enzyme intermediate blocks turnover of the enzyme [46] [47]. /3-Lactamase inhibitors can be divided into two classes, class I and class II class-I inhibitors (e.g., clavulanic acid (5.12)), in contrast to those of class II (e.g., olivanic acid (5.15)), have a heteroatom at position 1 that can lead to ring opening at C(5). The mechanistic consequences of this difference in structure are illustrated by the general scheme in Fig. 5.3. 

Application of the above screen led to the detection of a number of /8-lactamase inhibitors from a number of strains of Streptomyces olivaceus. They were identified as the carbapenem derivatives, MM 13902 (12), MM 4550 (13) and MM 17880 (14), known collectively as the olivanic acids [27, 28]. Not only are they potent -lactamase inhibitors, but are also powerful antibacterial agents. Subsequently, a whole series of carbapenem derivatives... 

The carbapenems are mechanism-based inhibitors which involve acylation of the active-site residue and subsequent rearrangement to a more stable acyl-enzyme species. Knowles and co-workers [32, 33] have demonstrated that the progressive inhibition of the TEM S-lactamase by the olivanic acids is due to the rearrangement of the J -pyrroline intermediate (15) to the tautomeric and thermodynamically more stable zl -pyrroline (16) Scheme 6.3). The resultant acyl-enzyme complex is believed to be stable to subsequent hydrolytic breakdown, thereby disrupting the catalytic activity of the enzyme. 

A short time after the isolation of the olivanic acids from Streptomyces olivaceus, Beecham scientists detected another potent y9-lactamase inhibitor in a culture of Streptomyces clavuligerus. This inhibitor was isolated and characterized as clavulanic acid (17) [34, 35]. Whilst this compound has only... 

The isolation of the olivanic acids and clavulanic acid from natural sources stimulated a worldwide search for yS-lactamase inhibitors with improved biological properties. Whilst much effort was devoted to the chemical modification of the olivanic acids and clavulanic acid, perhaps the greatest success has been achieved by the chemical manipulation of 6-aminopenicil-lanic acid (6-APA) (8) and penicillin G (4). The purpose of this review is to describe some of the successful efforts that have been made to design and synthesize potent inhibitors of bacterial S-lactamases from these readily available chiral synthons. 

Another approach used in the search for novel p-lactams has involved screening techniques designed to detect inhibitors of p-lactamase activity. Clavulanic acid and the olivanic acids were first detected in p-lactamase inhibitor screens (Brown et al., 1977 Butterworth et al., 1979). 

The microorganism Streptomyces olivaceus produces a number of P lactam antibiotics and P-lactamase inhibitors which have collectively become known as the olivanic acids 49, 69—75). Together with other streptomycete metabolites such as thienamycin 80, 81), PS-5 85, 86), the carpetimycins 90, 91) and the asparenomycins 92), they form a family of natural products characterised by the presence of the l-carbadethiapen-2-em (7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid) ring system (94). The simplest member of the family is the completely unsubstituted nucleus (94), recently isolated from various species of Serratia and Erwinia 98). All the other natural products possess substituents at C(2) and C(6) of this nucleus, the former being attached by way of a sulphur linkage. Differences in the nature and stereochemistry of these substituents have provided a wide variety of structures. Almost forty natural variations of this ring system are now known and these are listed in Table 5. 

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