Anti-infective strategies of the future: is there room for species-specific antibacterial agents?

Broad-spectrum antibiotics, directed against conserved bacterial targets, are the mainstay of antibacterial therapy. Increasing resistance, however, demands new strategies. Over time a number of therapeutic concepts have evolved, starting out with the use of polyclonal antisera, which were rapidly replaced by the easier to use antibiotics.

The targets of currently used antibacterial agents: lessons for drug discovery.

Based on the mode of action of antibacterial drugs currently used, targets can be defined as distinct cellular constituents such as enzymes, enzyme substrates, RNA, DNA, and membranes which exhibit very specific binding sites at the surface of these components or at the interface of macromolecular complexes assembled in the cell. Intriguingly, growth inhibition or even complete loss of bacterial viability is often the result of a cascade of events elicited upon treatment with an antibacterial agent. In addition, their mode of action frequently involves more than one single target.

New anti-MRSA and anti-VRE carbapenems; synthesis and structure-activity relationships of 1beta-methyl-2-(thiazol-2-ylthio)carbapenems.

Discovery of novel antimicrobial agents effective against infections caused by drug-resistant pathogens is an important objective. In order to find a new parenteral carbapenem antibiotic, which has potent antibacterial activity especially against methicillin-resistant staphylococci, vancomycin-resistant enterococci and penicillin-resistant Streptococcus pneumoniae, a series of 1beta-methylcarbapenems with thiazol-2-ylthio groups at the C-2 position have been synthesized. Structure-activity relationships were investigated which led to SM-197436 (27), SM-232721 (44) and SM-232724 (41), being selected for further evaluation.