In the last two decades, the prevalence of infections related to multidrug resistant bacterial strains has raised dramatically. Nowadays, 65% of the bacterial infections in hospital centres are due to six pathogens classified as ‘ESKAPE’ because they escape to the action of most of the antibacterial drugs available on the market by the mean of multiple resistance mechanisms. Developing new classes of antibacterial agents is therefore becoming one of the biggest challenges in human health for the next decade. The involvement of chemists in this process is of crucial importance, not only for the design of original structures, but also when it turns to the elucidation of their mechanisms of action or for the improvement of their physicochemical/pharmaceutical properties. We are currently developing two classes of synthetic compounds possessing some original structures and mechanisms of actions. In the course of these studies, our academic chemist points of views are confronted to problems with multiple variables on a regular basis. Some examples of this confrontation will be provided here.