0-Lactam antibiotics Subject

The mechanism of action of -lactam antibiotics has been the subject of several recent reviews <79MI51102, 79MI51103, 81MI51104, B-81MI51105, B-82MI51101). 

As a consequence of the increased resistance of bacteria to classical /3-lactam antibiotics, several strategies devoted to the synthesis of new bi- and polycyclic /3-lactam derivatives have been developed, giving rise to a large number of compounds featuring enhanced antibacterial activity or better resistance toward /3-lactamases. It is the aim of this section to extend previous accounts on this subject in CHEC(1984) and CHEC-II(1996) and to summarize several recent methodologies concerning the preparation of these fused heterocycles. 

Of the effective compodnds available at the present time, the )3-lactam antibiotics, the aminoglycosides and the polymyxins are all bacteriocidal. The j8-lactam antibiotics, notably carbenicillin, suffer primarily from the penetration factor but enzyme activity can play an important part. The aminoglycosides, on the other hand, have few or no penetration problems but are subject to enzymatic modification. The polymyxins penetrate to the active site and appear to be resistant to enzymatic modification. However, toxicity problems associated with polymyxin therapy prevent the widespread use of these drugs. 

Altered platelet numbers and function Platelet dysfunction occurs dose-dependently with carbenicillin, ticarcillin, and, infrequently, other broad-spectrum penicillins (105), but the NMTT cephalosporin moxalactam has also been associated with altered platelet function in both healthy subjects and in patients treated with standard regimens (106-110). In contrast, clinical studies including cefotaxime, ceftizoxime, cefoperazone, and ceftracone did not show platelet dysfunction attributable to these compounds (109-111). There is evidence that beta-lactam-antibiotic-induced platelet dysfunction is at least partially irreversible (112). 

Canadian data have partly confirmed these findings (169). Benzylpenicillin derivatives and semisynthetic penicillins were applied to 112 patients with a history of an allergic reaction to penicillins. The tests were positive in 21 patients (19%), of whom 10 reacted against the semisynthetic penicillin reagents only. Reports of subjects allergic to flucloxacillin (186), cloxacillin (187), and cefa-droxil (188), but not penicillin, lend further support to the concept of side chain-specific allergic reactions (see the monograph on beta-lactam antibiotics). 

The manner in which penicillin and other P-lactam antibiotics exert their action on bacterial cell walls has been the subject of elegant studies over the years [63]. In 1966, Tipper and Strominger [64] proposed an intriguing hypothesis whereby penicillin was presumed to exert its antibacterial action, in part, by mimicking the D-ala-D-ala moiety of a donor muramyl peptide in the tianspeptidation reaction during the formation of the cell wall. 

Also included in Volume 3 is a report (Chapter 5) written for the nonmedical scientist describing the clinical uses of the compounds that result from these efforts. The concluding chapters of Volume 3 review two new subjects that are currently at the forefront of p-lactam research. The first of these. Chapter 6, discusses the events that occur in the bacterial cells between cell wall biosynthesis inhibition and cell lysis. It addresses the problem of penicillin-tolerant strains that have the ability to survive in the presence of large amounts of p-lactam antibiotics. The last chapter (7) again turns to a newly discovered class of antibacterial P-lactam natural products. These newly discovered monocyclic compounds, called monobactams, appear to have clinical utility. 

This book encompasses the substantial additions made to our knowledge of p-lactam antibiotics since Cephalosporins and Penicillins Chemistry and Biology was published in 1972. But the editors asked for an introductory chapter that might indicate how this now immense subject came into being and that would point to some of the many characters in the story. The following account comes from my personal memories as well as from contemporary records, and reflects my own point of view. 

Since the time when the production of 6-APA and 7-ACA opened the door to a new era in the field of p-lactam antibiotics, the subject has been expanding with increasing momentum. The isolation of 7-a-meth-oxycephalosporins has been followed by the discovery of new p-lactams with interesting and potentially valuable properties which are neither penicillins nor cephalosporins and whose common feature is virtually restricted to a -lactam ring. The availability of many different -lactam antibiotics has made it possible to show that there are differences in the active sites of the various penicillin-sensitive enzymes in bacterial membranes and to reveal the existence of a multiplicity of J-lactamases, to which membrane enzymes may be related. 

The incidence of serious cardiac arrhythmia with the use of fluoroquinolones was investigated in a retrospective, nested case-controlled study. Fluoroquinolones were associated witir an increased risk of serious cardiac arrhythmia (RR 1.76) with gatifloxacin giving the highest risk (RR7.38), followed by moxifloxacin (RR 3.30) and ciprofloxacin (RR 2.15) [20 ]. Hypersensitivity reactions to fluoroquinolones are more likely in subjects who have had a previous reaction to beta-lactam antibiotics (OR 4.57) [21 ]. 

A priori, the poorest substrates for j8-lactamase may be considered as the most effective /8-lactam antibiotics. When subjected to antibiotic-selection pressure, however, the bacteria rapidly develop resistance via high frequency mutations either altering the structure and function of the enzyme toward broader (or extended) substrate specificities or overproducing the wild-type /8-lactamases (up-promoter mutations). 

Several review articles have appeared during the past two years. " The rearrangements of penicillanic acid derivatives have been the subject of one review, while the total synthesis of nuclear analogues of penicillin and cephalosporins and recent developments in the chemistry of the j3-lactam antibiotics have also been reviewed. " ... 

A major monograph covering many of the aspects of the biology and chemistry of cephalosporins and penicillins up to 1972 has appeared. The chemical interconversion of the 3-lactam antibiotics has been the subject of one review while a second covers the general synthetic methods for 3-lactams, inclucUng cephalosporins and penicillins. Earlier reviews on the mechanism by which 3-lactams effect their antibacterial activity and the structure-activity relationships of penicillins and cephalosporins" should be noted. 

The biosynthesis of the 3-lactam antibiotics continues to be a subject of considerable interest and speculation. The ring systems of both penicillin and cephalosporins have been shown to be formed from L-valine and... 

In accordance with intention expressed in the Preface to Volume 1 to give more detailed treatment to unusually important or topical subjects, a new chapter is introduced in this volume entitled 3-Lactam Antibiotics, Other Sulphur-containing Natural Products, and Related Compounds . 

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