Cascade Processes of Metallo Carbenoids

A novel beta-lactamase inhibitor has been isolated from Streptomyces clavuligerus ATCC 27064 and given the name clavulanic acid. Conditions for the cultivation of the organism and detection and isolation of clavulanic acid are described. This compound resembles the nucleus of a penicillin but differs in having no acylamino side chain, having oxygen instead of sulfur, and containing a beta-hydroxyethylidine substituent in the oxazolidine ring. Clavulanic acid is a potent inhibitor of many beta-lactamases, including those found in Escherichia coli (plasmid mediated), Klebsiella aerogenes, Proteus mirabilis, and Staphylococcus aureus, the inhibition being of a progressive type. The cephalosporinase type of beta-lactamase found in Pseudomonas aeruginosa and Enterobacter cloacae P99 and the chromosomally mediated beta-lactamase of E. coli are less well inhibited. The minimum inhibitory concentrations of ampicillin and cephaloridine against beta-lactamase-producing, penicillin-resistant strains of S. aureus, K. aerogenes, P. mirabilis, and E. coli have been shown to be considerably reduced by the addition of low concentrations of clavulanic acid.

Clavulanic Acid: a Beta-Lactamase-Inhibiting Beta-Lactam from Streptomyces clavuligerus

To create a drug, nature's blueprints often have to be improved through semisynthesis or total synthesis (chemical postevolution). Selected contributions from industrial and academic groups highlight the arduous but rewarding path from natural products to drugs. Principle modification types for natural products are discussed herein, such as decoration, substitution, and degradation. The biological, chemical, and socioeconomic environments of antibacterial research are dealt with in context. Natural products, many from soil organisms, have provided the majority of lead structures for marketed anti-infectives. Surprisingly, numerous "old" classes of antibacterial natural products have never been intensively explored by medicinal chemists. Nevertheless, research on antibacterial natural products is flagging. Apparently, the "old fashioned" natural products no longer fit into modern drug discovery. The handling of natural products is cumbersome, requiring nonstandardized workflows and extended timelines. Revisiting natural products with modern chemistry and target-finding tools from biology (reversed genomics) is one option for their revival.

Antibacterial Natural Products in Medicinal Chemistry—Exodus or Revival?

The industrial production of beta-lactam antibiotics by fermentation over the past 50 years is one of the outstanding examples of biotechnology. Today, the beta-lactam antibiotics, particularly penicillins and cephalosporins, represent the world's major biotechnology products with worldwide dosage form sales of approximately 15 billion US dollars or approximately 65% of the total world market for antibiotics. Over the past five decades, major improvements in the productivity of the producer organisms, Penicillium chrysogenum and Acremonium chrysogenum (syn. Cephalosporium acremonium) and improved fermentation technology have culminated in enhanced productivity and substantial cost reduction. Major fermentation producers are now estimated to record harvest titers of 40-50 g/l for penicillin and 20-25 g/l for cephalosporin C. Recovery yields for penicillin G or penicillin V are now >90%. Chemical and enzymatic hydrolysis process technology for 6-aminopenicillanic acid or 7-aminocephalosporanic acid is also highly efficient (approximately 80-90%) with new enzyme technology leading to major cost reductions over the past decade. Europe remains the dominant manufacturing area for both penicillins and cephalosporins. However, due to ever increasing labor, energy and raw material costs, more bulk manufacturing is moving to the Far East, with China, Korea and India becoming major production countries with dosage form filling becoming more dominant in Puerto Rico and in Ireland.

Industrial production of β-lactam antibiotics

The continued emergence of multi-drug-resistant bacteria is a major public health concern. The identification and development of new antibiotics, especially those with new modes of action, is imperative to help treat these infections. This review lists the 22 new antibiotics launched since 2000 and details the two first-in-class antibiotics, fidaxomicin (1) and bedaquiline (2), launched in 2011 and 2012, respectively. The development status, mode of action, spectra of activity, historical discovery and origin of the drug pharmacophore (natural product, natural product derived, synthetic or protein/mammalian peptide) of the 49 compounds and 6 β-lactamase/β-lactam combinations in active clinical development are discussed, as well as compounds that have been discontinued from clinical development since 2011. New antibacterial pharmacophore templates are also reviewed and analyzed.

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Antibiotics in the clinical pipeline in 2013

The structure of clavulanic acid, a β-lactamase inhibitor isolated from Streptomyces clavuligerus, has been shown by spectroscopic methods and X-ray analysis to be a novel fused β-lactam.

Clavulanic acid, a novel β-lactam isolated from Streptomyces clavuligerus; X-ray crystal structure analysis

The structures of two new, naturally occurring β-lactams are proposed on the basis of spectroscopic properties, and their interconversion.

Structures of olivanic acid derivatives MM 4550 and MM 13902; two new, fused β-lactams isolated from Streptomyces olivaceus

The structure of the olivanic acid derivative (1) has been confirmed by a novel β-lactam degradation in dimethyl sulphoxide; application of this reaction has resulted in the structure elucidation of a new antibiotic, MM 17880.

Structure elucidation of MM 17880, a new fused β-lactam antibiotic isolated from Streptomyces olivaceus; a mild β-lactam degradation reaction

CLAVULANIC ACID, A NOVEL β-LACTAM ISOLATED FROM STREPTOMYCES CLAVULIGERUS, X-RAY CRYSTAL STRUCTURE ANALYSIS

Ethyl 3-methyl-7-oxo-4-oxa-1-azobicylco[3.2.0]-hept-2-ene-2-carboxylate (4) has been obtained by a four-step synthesis from 4-methylthioazetidin-2-one and has been compared with the products obtained from the rhodium(II) acetate-catalysed reaction of 4-acetoxy-azetidin-2-one with ethyl α-diazoacetoacetate; this latter reaction did not give compound (4), as was previously claimed, but yielded ethyl 2-(4-acetoxy-2-oxoazetidinyl)-3-oxobutyrate as the major β-lactam product.

Synthesis of ethyl 3-methyl-7-oxo-4-oxo-4-oxa-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate and the reaction of 4-acetoxyazetidin-2-one with ethyl α-diazoacetoacetate

T. Trefor Howarth

Papers

Clavulanic acid, a novel β-lactam isolated from Streptomyces clavuligerus; X-ray crystal structure analysis

Structures of olivanic acid derivatives MM 4550 and MM 13902; two new, fused β-lactams isolated from Streptomyces olivaceus

Structure elucidation of MM 17880, a new fused β-lactam antibiotic isolated from Streptomyces olivaceus; a mild β-lactam degradation reaction

CLAVULANIC ACID, A NOVEL β-LACTAM ISOLATED FROM STREPTOMYCES CLAVULIGERUS, X-RAY CRYSTAL STRUCTURE ANALYSIS

Synthesis of ethyl 3-methyl-7-oxo-4-oxo-4-oxa-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate and the reaction of 4-acetoxyazetidin-2-one with ethyl α-diazoacetoacetate