New trends in antimicrobial development.

So far, two strategies have been applied to develop new anti-infective agents: (a) the synthesis of analogs of classical antibiotics with enhanced activity against resistant pathogens and (b) the screening of naturally occurring substances and libraries of synthetic compounds for antimicrobial activity in whole-cell assays. Today, the same principles are being used; however, the search for antimicrobial compounds with novel modes of action is based on targeting specific resistance and virulence factors. Novel targets for anti-infective agents are currently being discovered as a consequence of a better understanding of cell biology, the molecular basis of bacterial resistance, the gene-pathogenicity relationship and the mechanism of the infection process.

Recent advances in the chemistry of beta-lactam compounds as selected active-site serine beta-lactamase inhibitors.

The b-lactamases catalyze the hydrolysis of the b-lactam bond of a variety of b-lactam antibiotics destroying their antibacterial activity. During the last decades, there has been an inexorable spread of b-lactamase genes into species that previously were not known to possess them. One approach to combat the action of the b-lactamase is to inhibit the enzyme. However, inhibition of b-lactamase alone is not sufficient. The ability to penetrate the external membrane of Gram-negative bacteria, chemical stability, pharmacokinetics and other factors are also important in determining whether an inhibitor is suitable or not for therapeutic use. This review takes recent examples of synthetic b-lactam compounds developed as active-site serine b-lactamase inhibitors, emphasizing information on their structures and their activity against Ambler classes A, C and D b-lactamases. In addition, examples based on rational design by computerized molecular modeling of crystal structure of the native enzyme and mechanism of the enzyme action are highlighted.

New trends in antimicrobial development.

The continual evolution of microbial resistance to the available classes of antibiotics poses a serious threat to the efficacy of traditional antibacterial therapy. Today, there are two main approaches that are being applied to discover better and more effective anti-infective agents against common as well as resistant pathogens: (a) the improvement of the "classical" antimicrobial agents by targeting the so called "resistance factors", and (b) the search of new anti-infective agents with novel modes of actions. This review will highlight the most relevant aspects of both of these approaches and some of the latest findings in the field of antimicrobial discovery.

Chemical modification of tazobactam. Synthesis of 2 beta-[(4-substituted)-1,2,3-triazol-1-yl]methyl penicillanic acid sulfone derivatives.

A series of 2 beta-[(4-substituted)-1,2,3-triazol-1-yl] methyl penicillanic acid sulfones was synthesized as beta-lactamase inhibitors. Many of these compounds showed good in vitro inhibitory activity against penicillinase, cefotaximase and plasmid-mediated class III TEM enzymes, but exhibited weaker cephalosporinase inhibition. One member in this series--2 beta-[(4-pyridiniummethyl)-1,2,3-triazol- 1-yl]-6,6-dihydropenicillanate 1,1-dioxide (12a), when tested in combination with piperacillin, showed excellent synergistic activity against microorganisms producing plasmid-mediated enzymes, but had insufficient activity against microorganisms producing chromosomally mediated class I enzymes.