There has been remarkable progress in the development of new antimicrobial agents as the result of structural modifications of the cephalosporin nucleus. It has been possible to predict many aspects of the antimicrobial activity of new agents and to recognize the structural modifications that contribute to overcoming the continued problem of bacterial resistance. The activity of beta-lactams against gram-positive species depends primarily on their affinity for the enzymes referred to as penicillin-binding proteins. Resistance of gram-positive species to beta-lactams is either due to altered penicillin-binding proteins or, more commonly, due to the presence of beta-lactamases, which are usually plasmid-mediated and inducible. The activity of beta-lactams against gram-negative aerobic and anaerobic bacteria is the result of the way in which the compounds pass through the porin channels in the outer wall, resist inactivation by beta-lactamases, and bind to the penicillin-binding proteins. The basic cephalosporin nucleus consists of the essential beta-lactam ring fused to a dihydrothiazine ring. It is possible to modify this structure to increase antibacterial activity. Changes in moieties at position 3 affect pharmacologic activity but can also cause a marked increase or decrease in activity against staphylococci and Pseudomonas species. The presence of the thiomethyltetrazole group at position 3 has been associated with an alteration in prothrombin synthesis and with disulfiram reactions. Modifications of the cephem nucleus at position 7 by addition of methoxy groups increase beta-lactamase stability but decrease activity against gram-positive species because of lower affinity for penicillin-binding proteins. The more useful acyl side chains have been those that contain a 2-aminothiazolyl moiety, which causes increased affinity of the molecules for penicillin-binding proteins of gram-negative bacteria and streptococcal species. Iminomethoxy groups provide beta-lactamase stability against the common plasmid beta-lactamases such as those of Staphylococcus aureus and the TEM, SHV-1, OXA, and PSE enzymes found in Enterobacteriaceae and Pseudomonas aeruginosa, as well as the chromosomally mediated K-1 and P99 enzymes of Enterobacter. A propylcarboxy group increases beta-lactamases stability and also provides activity against P. aeruginosa and some Acinetobacter. Conversely, this particular grouping reduces the beta-lactamase induction capabilities of a compound, as well as its ability to function as a beta-lactamase inhibitor.(ABSTRACT TRUNCATED AT 400 WORDS)