Methicillin-resistance in Staphylococcus aureus - molecular basis, novel targets and antibiotic therapy

Methicillin-resistant S. aureus are the major cause of nosocomial bacteremias showing a high morbidity rate in intensive care units. These strains are often resistant against almost all antibiotics in clinical use with the exception of vancomycin. However, the first isolation of a S. aureus strain with a diminished susceptibility to vancomycin from a hospitalized patient in Japan has been reported very recently. Therefore, current antibiotic therapy is difficult and expensive, often a combination of several antibiotics has to be used. For this reason novel antibiotics to combat staphylococcal bacteremias, which prevent further spread of resistance are urgently needed. One approach might be the investigation of the mechanism of methicillin resistance, which is mediated by PBP2a, an additional penicillin-binding protein present in resistant strains with low affinity to ss-lactams. Beside PBP2a other housekeeping genes, the so called fem factors, are involved in expression of methicillin resistance. Two of these fem factors, the FemAB proteins, have been shown to participate in the formation of the pentaglycine crossbridge, which is a unique staphylococcal cell wall component. The biosynthesis of the pentaglycine side chains is not fully elucidated, but follows an interesting novel mechanism with unusual glycyl-tRNA as a substrate. Furthermore, inactivation of femAB, which have been reported as essential for bacterial growth, causes a completely restoration of antibiotic susceptibility in MRSA strains. Thus, these proteins might serve as attractive novel anti-staphylococcal targets for a small-range antibiotic.