Jerome Birnbaum

Carbapenems, a new class of beta-lactam antibiotics: Discovery and development of imipenem/cilastatin

The discovery of Streptomyces cattleya and its antibiotic product, thienamycin, has ushered in a new era of beta-lactam agents, the carbapenems. Numerous carbapenems were subsequently discovered; however, none had the potency, broad-spectrum activity, and lack of cross-resistance exhibited by thienamycin. Chemical instability encountered with thienamycin was overcome by the N-formimidoyl derivative, imipenem. Imipenem is distinguished from other beta-lactams by its outstanding activity against gram-positive organisms as well as against Enterobacteriaceae, Pseudomonas aeruginosa, and Bacteroides. However, development was hindered by extensive renal metabolism of imipenem, resulting in low urinary concentrations of antibiotic. A renal dipeptidase, dehydropeptidase-I, was responsible for hydrolyzing imipenem and other carbapenems. To counter its action, a specific inhibitor, cilastatin, was developed. Coadministered with imipenem in a one-to-one ratio, cilastatin provides prolonged, reversible blockade of imipenem metabolism, dramatically improving urinary recoveries to therapeutically significant levels. Cilastatin also contributes to the safety of imipenem, since its coadministration prevents proximal tubular necrosis which has been observed in sensitive animals receiving imipenem alone in high doses. Thus, the combination imipenem and cilastatin overcame the pharmaceutical and metabolic challenges presented by thienamycin, and allowed for the evaluation in humans of the outstanding antimicrobial activity of this new class of beta-lactam antibiotics.

Coenzyme repression of acetyl-CoA carboxylase by (+)-biotin

Abstract Cell-free sonicated suspensions of L. plantarum were found to have acetyl-CoA carboxylase activity. The product of the reaction, which required ATP, acetyl-CoA and MnCl2 for maximum activity, was identified as malonyl-CoA. Avidin completely inhibited the reaction; the avidin effect was reversed by (+)-biotin. Heated cell extracts had no activity. Citrate and α-glycerophosphate, substances known to activate this enzyme in other organisms, had no effect. Apparent enzyme activity was low in cells grown in levels of (+)-biotin sufficient to support maximum growth. Biotin-deficient and biotin-excess cells showed lower and higher activities respectively. Saturation of biotin-deficient and biotin-sufficient cells with the vitamin, before preparation of extracts, greatly increased activity, whereas no increase was observed after saturation of cells grown with excess biotin. This demonstrated that a major portion of the enzyme in cells grown in sufficient and deficient levels of (+)-biotin is the apoenzyme form; the enzyme of cells grown in excess (+)-biotin is completely in the holoenzyme form. More importantly, the level of apo-acetyl-CoA carboxylase is controlled by the (+)-biotin concentration of the growth medium. Cells grown in excess or sufficient (+)-biotin contained only 20 and 30%, respectively, of the total enzyme (holo-plus apoenzyme) content of deficient cells. Apparently, the coenzyme, (+)-biotin, regulates the level of the protein moiety of the acetyl-CoA carboxylase enzyme. This regulatory mechanism has been termed “coenzyme repression.”

Development of the semisynthetic cephamycin, cefoxitin, as a clinical candidate

SummaryThe discovery of the cephamycin family of antibiotics represents a major advance in beta-lactam chemistry. The family provided an important intermediate for the synthesis of a group of antibiotics with outstandingly good resistance to beta-lactamase. Cefoxitin is the first of these semisynthetic cephamycins to be made available for clinical use. Extensive laboratory studies show that cefoxitin provides a significant advance over currently in use beta-lactam antibiotics. It has a broader spectrum than the cephalosporins and, in addition, is active against many strains of indolepositiveProteus, Serratia spp. andBacteroides spp., includingBacteroides fragilis and all its subspecies. It is active against many strains ofEscherichia coli andKlebsiella that have become resistant to the cephalosporins. The broader spectrum can be accounted for in large measure by cefoxitins almost complete resistance to a wide range of beta-lactamases. Cefoxitin is bactericidal, is unaffected by inoculum size and is metabolically stable; it is, therefore, a highly reliable antibiotic for usein vivo. Animal experiments have shown the excellent correlation betweenin vitro susceptibility andin vivo efficacy with cefoxitin. Excellent efficacy, safety and reliability of cefoxitin make this antibiotic useful in the treatment of a very broad range of infections.ZusammenfassungDie Entwicklung der Cephamycin-Antibiotika stellt einen großen Fortschritt in der Beta-Laktam-Chemie dar. Diese Antibiotika-Familie lieferte ein wichtiges Bauelement für die Synthese einer Gruppe von Antibiotika mit außergewöhnlich guter Beta-Laktamase-Festigkeit. Cefoxitin ist das erste klinisch anwendbare halbsynthetische Cephamycin. Umfangreiche In-vitro-Studien zeigen, daß Cefoxitin einen bedeutenden Fortschritt gegenüber den bisher verwendeten Beta-Laktam-Antibiotika aufweist. Es besitzt ein breiteres Wirkungsspektrum als die Cephalosporine und ist außerdem wirksam gegen viele Bakterienarten der indolpositvenProteus-,Serratia- undBacteroides-Gruppen, einschließlichBacteroides fragilis und dessen Arten. Die antimikrobielle Wirksamkeit von Cefoxitin umfaßt auch die BakteriengruppenEscherichia coli undKlebsiella, die gegen Cephalosporine resistent wurden. Das breitere Wirkungsspektrum kann größtenteils der beinahe absoluten Beta-Laktamase-Festigkeit zugeschrieben werden. Cefoxitin wirkt bakterizid, unabhängig von der Größe des Inokulums, und ist metabolisch stabil; es ist damit ein außergewöhnlich zuverlässiges Antibiotikum für den klinischen Gebrauch. Tierversuche mit Cefoxitin zeigten die hervorragende Korrelation zwischen der In-vitro- und In-vivo-Wirksamkeit. Große Wirksamkeit, hohe Sicherheit und Zuverlässigkeit machen Cefoxitin zu einem wertvollen Antibiotikum mit sehr breitem Spektrum.