Richard B. Sykes

Beta-lactam antibiotics

Beta-lactam drugs, whose mechanism of action is inhibition of the last stage of bacterial cell wall synthesis, are the largest family of antimicrobial agents and the most widely used in current clinical practice. These drugs have a slow, time-dependent bactericidal action, generally good distribution in the body, and low toxicity. Modifications of the original molecule have led to new compounds with a greater antimicrobial spectrum and activity; nonetheless, the use and efficacy of beta-lactams is limited in some clinical settings, owing to the increasing emergence of antimicrobial resistance. Despite this problem, penicillin remains the treatment of choice in a large number of infections, cephalosporins have a wide range of indications, carbapenems are used in nosocomially-acquired infection and infection caused by multiresistant microorganisms, and beta-lactam inhibitors restore the spectrum of activity of their companion penicillins (aminopenicillins, ureidopenicillins) when resistance is caused by beta lactamase production.

The New Monobactams: Chemistry and Biology

The discovery of the monobactams led to the successful development of aztreonam as the first of this novel class of beta‐lactam antibiotics to enter the clinical field. Continued structural modification on the monobactam nucleus has resulted in two additional compounds from this class that show interesting biologic properties. The first, SQ 83,360, is like aztreonam in exhibiting high activity against members of the Enterobacteriaceae but has the added characteristic of being exceptionally active against strains of Pseudomonas aeruginosa. Also, significant gains are made with SQ 83,360 in activity against Pseudomonas spp. and Acinetobacter. The second compound, tigemonam, is also like aztreonam, having good activity against Enterobacteriaceae, Haemophilus influenzae, and Neisseria gonorrhoeae and showing good beta‐lactam stability. Tigemonam differs from aztreonam in being well absorbed orally by experimental laboratory animals.

Naturally Occurring Monobactams

Publisher Summary The naturally occurring monobactams discovered to date are uniformly poor antibiotics that afford in themselves no opportunity for clinical utility. However, the monobactam nucleus and analogs with a variety of substituents in the 1-, 3-, and 4-positions of the azetidinone ring are readily accessible by synthesis. This highly active area of research has been the subject of recent reviews. A number of synthetic analogs that have excellent antimicrobial activity in vivo have been developed. Aztreonam, the first synthetic monobactam to undergo clinical trials, has entered the market, and a second synthetic monobactam, AMA 1080, is presently undergoing clinical trials. Both of these antimicrobial agents are useful for treating gram-negative bacterial infections by parenteral administration. An orally active prodrug, SQ 82,531, has been described and is presently undergoing clinical evaluation. This agent illustrates an alternative mode of providing activation of the β-lactam and (after enzymatic hydrolysis to SQ 82,291) an anionic binding site. Because of the great synthetic flexibility inherent in the monobactam system, it is probable that further clinically useful antimicrobial agents will follow.

Physiology, Biochemistry, and Inactivation of β - Lactamases

Publisher Summary This chapter focuses on the physiology, biochemistry, and inactivation of β-lactamases. The significance of β-lactamase in the resistance of pathogens to treatment by β-lactam antibiotics has been the subject of considerable controversy. The activity of a particular β-lactam antibiotic on a particular bacterial strain is often the result of a complex combination of factors in which β-lactamase may play a variety of roles. The factors to be considered in β-lactam-cell interactions include permeability or penetrability, nonlethal binding, susceptibility of target sites, and lytic response. The overall importance of β-lactamase in the response of a bacterial strain to a particular antibiotic is, thus, based on the capacity of the enzyme to complement the basic tolerance or to compensate for a lack of it. β-lactamases hydrolyze the cyclic amide bond in β-lactam-containing molecules such as penicillins and cephalosporins. When the β-lactam ring of a penicillin is hydrolyzed by β-lactamase, the corresponding antibiotically inactive penicilloate is produced in stoichiometric proportions. The first product of β-lactamase attack on a cephalosporin is, hypothetically, a cephalosporoate analogous to penicilloates. Thus, although the determination of the rate of hydrolysis of penicillins by β-lactamases is a relatively simple matter, the situation with cephalosporins is more complex.

Activity of sulfa drugs and dihydrofolate reductase inhibitors againstCandida albicans

Growth ofCandida albicans can be inhibited by sulfa drugs which prevent biosynthesis of folic acid. The dihydrofolate reductase (E.C. 1.5.1.3) inhibitors aminopterin and methotrexate also exhibit anticandidal activity, but trimethoprim does not. Kinetic evaluations withC. albicans dihydrofolate reductase indicate that methotrexate and aminopterin are tight-binding inhibitors whereas trimethoprim binds poorly.