[Antibiotic transport and membrane permeability: new insights to fight bacterial resistance].

A main challenge in medicinal chemistry is to determine the parameters modulating the in cellulo drug concentration needed for a therapeutic action. In Gram-negative antibacterial research, the concern is to evaluate the antibiotic permeation across the outer and inner membranes, that delineate the periplasm surrounding the bacterial cytoplasm. Passing through the membrane barrier to reach the inhibitory concentration inside the bacterium is the first pivotal step for antibiotics. The research and the development of new antimicrobials mostly rely on their capacity to reach critical concentrations in the vicinity of their intracellular target. Despite several decades of studies focused on antibiotic/drug activity against bacterial cells using different approaches, no consensus regarding the analysis of the kinetics and accumulation in individual bacterium and in bacterial populations is available to understand the drug translocation into living bacteria as a first step of drug action. Our TRANSLOCATION consortium supports the development of reliable and robust methods to quantify penetration and efflux processes in Gram-negative bacteria and recently we have developed a reliable and efficient method to determine the intra-bacterial concentration of fluorescent antibiotics. By using these powerful approaches, new concepts, "Resident Time Concentration Close to Target" (RTC2T) and "Structure Intracellular Concentration Activity Relationship" (SICAR), have been proposed in order to link chemical and structural aspects with the bacterial membrane and transport aspects. Using RTC2T and SICAR indexes, a new dissection of antibiotic translocation-transport can be obtained to better understand and improve the antibiotic pharmacophoric groups that are related to permeation and efflux.