Classes Of Β-lactam Antibiotics Research Articles

Overview of the development of a new class of β-lactam antibiotics: The carbacephems

Overview of the development of a new class of β-lactam antibiotics: The carbacephems

The carbacephems: A new beta-lactam antibiotic class

The carbacephems are a new class of β-lactam antibiotics that are similar in structure to the cephalosporins. Carbacephems differ from cephalosporins, however, in the substitution of a sulfur atom in the dihydrothiazine ring with a methylene group to form a tetrahydropyridine ring. The result of this structural difference is the carbacephem class. Carbacephems have remarkable chemical stability that allows for structural manipulation in a manner that could not be done previously with the cephalosporin ring system. Potent broad-spectrum antibiotics result from the incorporation at the 3 position of substituents that include quaternary pyridinium or imidazole, sulfones, and heterocyclic thiazole structures. Because of the chemical stability of the carbacephems, these highly electronegative side chains can be added to the 3 or 3′ position of the tetrahydropyridine ring system. Increasing the electronegativity of these side chains can increase the microbiologic activity of the compounds. In addition, utilizing the side chains that have traditionally conferred good oral absorption on the cephalosporins offers the possibility of a new series of broad-spectrum oral antibiotics. Loracarbef is the first carbacephem to undergo clinical development, and other experimental carbacephems are being produced with the aim of developing potent oral antibiotics that can be used against pathogens that cause infections commonly found in the outpatient setting.

▾ Imipenem + cilastatin – a new type of antibiotic

Imipenem is the first of the carbapenems – a new class of β-lactam antibiotics. It is combined with cilastatin, a non-antibiotic enzyme inhibitor which prevents the breakdown of imipenem to nephrotoxic metabolites. The combination (Primaxin – MSD) is available only for intravenous use. Imipenem has an unusually wide spectrum of activity covering most Gram-positive and Gram-negative bacteria including cephalosporin-resistant strains and anaerobes. Empirical use as the sole antibiotic in severe infections and as definitive treatment of unusually resistant bacteria is tempting.

Imipenem cross-reactivity with penicillin in humans

We examined the potential for IgE-mediated cross-reactivity between the carbepenems, a new class of β-lactam antibiotics, represented by imipenem, and penicillins. In vivo skin testing with the relevant imipenem and penicillin determinants was undertaken. Having determined the concentrations of imipenem materials that did not induce false positive skin tests in nonpenicillin-allergic control subjects, we tested 40 subjects with a history of penicillin-allergic reactions. Twenty of these subjects were found to be nonallergic to penicillin on skin testing, and none of these subjects reacted to the imipendem determinants. In contrast, half the 20 subjects who were positive to one or more penicillin determinants also reacted to imipenem reagents. There was a good correlation between the penicillin and imipenem reagents to which the patients reacted. Imipenem should only be administered to penicillin-allergic subjects with similar precautions of penicillin administration to such patients.

A highly asymmetric synthesis of the O-2-isocephem class of β-lactam antibiotics

Starting from D-threonine, an asymmetric synthesis of the dextrorotatory bioactive enantiomer of 3-methyl-7-phenylacetamido-O-2-isocephem was accomplished. The key step, where asymmetric cycloaddition of azidoacetyl chloride to the cinnamylidene Schiff base of protected D-threonine is induced, generates the desired cis-β-lactam in 90% optical yield. The absolute configuration of the final product was confirmed by comparing its antimicrobial activity with that of its corresponding racemate.

ChemInform Abstract: NUCLEAR ANALOGS OF β‐LACTAM ANTIBIOTICS. II. SYNTHESIS OF O‐2‐ISOCEPHEMS

AbstractDas aus (Ia) erhältliche Mesylat (Ib) wird zur Verbindung (II) enolisiert, deren Cyclisierung das Azido‐cephem (IIIa) liefert.

Nuclear analogs of β-lactam antibiotics. II. Synthesis of O-2-isocephems

The preparation by total synthesis of a new class of β-lactam antibiotics is reported. Conversion of alcohol 1b to its mesylate 9b followed by hydrolysis of the acetal to the enol 1b and base-catalyzed ring closure gave benzyl 7- β-azido-Δ3-O-2-isocephem-4-carboxylate 8b. Similarly prepared were the 3 -methyl, 3 -benzyl, and 3 -phenethyl analogs (32b–d). Reduction of the azides followed by coupling of the resultant amines with phenoxyacetic acid and removal of the benzyl groups by hydrogenolysis gave the acids 35a–e which exhibited high antibacterial activity. The structural assignments to the O-2-isocephems which were made on the basis of their spectral characteristics (ir, uv, and nmr) are discussed.