Comparison of fortimicins with other aminoglycosides and effects on bacterial ribosome and protein synthesis

Abstract

Fortimicins are bicyclic aminoglycoside antibiotics that contain a fortamine moiety instead of the deoxystreptamine found in other aminoglysides. Fortimicin A had a bactericidal effect on Escherichia coli and Staphylococcus epidermnidis and was found to inhibit protein synthesis in vivo. In vitro, fortimicin A inhibited polyuridylic acid-directed phenylalanine polymerization and induced misreading, as shown by leucine incorporation. In contrast, fortimicin B had no effect on either polymerization or misreading. In assays programmed with natural mRNA, only a weak polymerization inhibition effect was observed with fortimicin A, whereas a strong stimulation was seen in the presence of fortimicin B. inactivation, has prompted us to explore the mode of action of fortimicins. Fortimicins are structurally different from major aminoglycosides, since they incorporate fortamine, a novel aminocyclitol moiety, instead of 2-deoxystreptamine. To our knowledge, no study dealing with the mode of action of molecules from this series has been published. It was therefore interesting to carry out such a study, and it would not be surprising to find that the mode of action of these molecules, although related, differs from that of the other aminoglycosides. As a matter of fact, it is well known (24) that streptomycin and apramycin, which are structurally different from major aminoglycosides, exert different effects on protein synthesis. Moreover, it is now well documented (9, 18) that even the aminoglycosides of the deoxystreptamine group do not share either a common binding site or a common mode of action on the bacterial ribosome.This work is divided into three parts: (i) effects on whole bacteria, (ii) study of biosyntheses in vitro; and (iii) binding to the bacterial ribosome.MATERIALS AND METHODS Materials. Materials were obtained from the following sources: fortimicins A and B, Abbott Laboratories; gentamicin C, Unilabo; kanamycin A, Allard-Bristol; tobramycin, Eli Lilly & Co.; neomycin B, Roussel-Uclaf; streptomycin, Rhone Poulenc.

The unusual mode of action of the polyketide glycoside antibiotic cervimycin C

“…Nevertheless, the test systems used here would be incapable of detecting mistranslation at the ribosome, which, therefore, cannot be excluded for cervimycin. Aminoglycosides induce misreading at relatively low concentrations, 2 × MIC, while much higher concentrations are needed to inhibit protein biosynthesis in vivo (35 × MIC) ( 63 , 64 ). The bactericidal effect of aminoglycosides is thought to rely on faulty membrane proteins causing membrane damage ( 65 ).…”

Recent progress on the development of antibiotics from the genus Micromonospora

“…Girolami et al (1977), showed that the antibacterial effect of fortimicin A against Enterobacteriaceae is comparable to amikacin [71]. Other research reported also the bactericidal effect of Fortimicin A against Staphylococcus epidermnidis [72]. Antlermicins A, B and C are antitumor antibiotics produced by soil isolate of M.…”

Micromonospora: A Prolific Source of Bioactive Secondary Metabolites with Therapeutic Potential

“…olivoasterospora. − To the best of our knowledge, 23 natural fortimicins (FTMs) or FTM epimers ( 54 – 76 ) have been isolated and identified as of 2021 (Figure ). ,− FTM A ( 54 ) from the soil-derived strain ATCC 2189 had a bactericidal effect on Escherichia coli and Staphylococcus epidermidis by inhibiting protein synthesis in vivo . It also showed excellent activity against Enterobacteriaceae strains compared to those of amikacin, gentamicin, sagamicin, and tobramycin .…”