[Evaluation of in vitro antibacterial activity of fosmidomycin and its derivatives]

Unlike the mammals, some species of pathogenic microorganisms synthesize isoprenoids by the mevalonate-independent pathway known as the methyl-erythritol phosphate pathway (MEP). The macromolecules of the polyprenyl compounds play an essential role in the metabolism of the microbial cell. Therefore, the MEP enzymes can be targets for new antibiotics. Antibacterial activity of fosmidomycin, an inhibitor of 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR), the key enzyme of MEP in isoprenoid biosynthesis was estimated. By the results of the in vitro experiments the tested microorganisms were divided into susceptible and resistant to fosmidomycin. Vaccinal strains of B. anthracis and practically all the strains of P. aeruginosa were included into the first group. The minimum inhibitory concentrations of fosmidomycin for them determined by the method of serial dilutions were 1-8 mcg/ml. The second group for which the MICs were 16-64 mcg/ml included representatives of Listeria, Yersinia and Burkholderia. The tested species of enteric bacteria, Mycobacterium, Corynebacterium, Campylobacterium and the tularemia vaccinal strain were fosmidomycin resistant. The MICs for them varied from 128 to 512 mcg/ml. Since all the above mentioned bacteria have DXR, resistance to fosmidomycin was conjectured with the difficulty of its delivery to the target in the microbial cell. To increase penetrability of fosmidomycin, various functional groups modifing its hydrophoby were added to the antibiotic molecule. However, no expected increase of the susceptibility to the derivatives was achieved probably because their affinity to DXR lowered. Penetrability of fosmidomycin to the cell was facilitated by using its combinations with compounds influencing the integrity of the bacterial cell membrane. Combined use of fosmidomycin with polymyxin B, chlorhexidine and cetrimide 4-64 times lowered its MICs for the strains of Listeria, Burkholderia and Yersinia.