Fluorinated Aminoglycosides and Their Mechanistic Implication for Aminoglycoside 3‘-Phosphotransferases from Gram-Negative Bacteria
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Abstract:
Aminoglycoside 3'-phosphotransferases [APH(3')s] are important bacterial resistance enzymes for aminoglycoside antibiotics. These enzymes phosphorylate the 3'-hydroxyl of these antibiotics, a reaction that inactivates the drug. A series of experiments were carried out to shed light on the details of the turnover chemistry by these enzymes. Quench-flow pre-steady-state kinetic analyses of the reactions of Gram-negative APH(3') types Ia and IIa with kanamycin A, neamine, and their respective difluorinated analogues 4'-deoxy-4',4'-difluorokanamycin A and 4'-deoxy-4',4'-difluoroneamine were carried out, in conjunction with measurements of thio effect and viscosity studies. The fluorinated analogues were shown to be severely impaired as substrates for these enzymes. The magnitude of the effect of the impairment of the fluorinated substrates was in the same range as when the D198A mutant APH(3')-Ia was studied with nonfluorinated substrates. Residue 198 is the proposed active site base that promotes the aminoglycoside hydroxyl for phosphorylation. These findings collectively argue that the Gram-negative APH(3')s show significant nucleophilic participation in the transition state for the phosphate transfer reaction.Keywords:
Phosphotransferases
Kanamycin
Phosphotransferases
[Objective] To evaluate the effect of eight aminoglycoside antibiotics against mycobacteria. [Methods] Minimal inhibitory concentration (MIC) of eight aminoglycoside antibiotics against twenty mycobacteria species in vitro were determined respectively. [Results] The various drugs show different antibacterial effect spectrum in vitro. [Conclusion] Aminoglycoside antibiotics are selection drugs in the treatment of nontuberculosis mycobacterial diseases clinically.
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The severe ototoxic interaction of the combined administration of furosemide and aminoglycoside antibiotics (kanamycin, streptomycin and gentamicin) was studied in rabbits, and its mechanism clarified. Severe damage occurred not only in the inner ear but also in the kidney when both furosemide and aminoglycoside antibiotics were administered to rabbits. Kanamycin concentration after a single injection of kanamycin with furosemide was much higher not only in the perilymph but also in the cerebrospinal fluid and serum than that after a single injection of kanamycin alone. The ototoxic interaction following the combined use of furosemide and aminoglycoside antibiotics seems to be caused mainly by the inhibitory effect of furosemide on the excretion of aminoglycoside antibiotics from the kidneys.
Kanamycin
Perilymph
Ototoxicity
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Aminoglycoside antibiotics are a kinds of early discovered and applied clinical antibiotics. Although they have not completely disappeared from the market,along with the emergence of broad spectrum antibiotics with fewer side effects,its importance has diminished. At present,due to the infection caused by multidrug resistant( MDR) bacteria increased dramatically,as one of the few treatment options,aminoglycoside antibiotics are back to peoples vision,especially for Gramnegative bacterial infection. Although their resistance mechanism has been basically clear,the understanding of antibacterial mode is far from comprehensive. Facing more and more virtually untreatable infections,this kind of old antibiotics would have application potential to combat multi-drug resistant pathogens.
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Kanamycin
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Phosphotransferases
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Phosphotransferases
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In an effort to optimize the antibacterial activity of kanamycin class aminoglycoside antibiotics, we have accomplished the synthesis and antibacterial assay of new kanamycin B analogues. A rationale-based glycodiversification strategy was employed. The activity of the lead is comparable to that of commercially available kanamycin. These new members, however, were found to be inactive against aminoglycoside resistant bacteria. Molecular modeling was used to provide the explanation. Thus, a new strategy for structural modifications of kanamycin class aminoglycosides is suggested.
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Kanamycin
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Against more than 90% of 200 bacterial strains tested in vitro, the inhibitory concentration of gentamicin and tobramycin was 3.1 μg/ml and that of BB-K 8, a new semisynthetic aminoglycoside derivative of kanamycin, was 6.3 μg/ml.
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Aminoglycosides are an important resource against infectious diseases. However, the prevalence of aminoglycoside resistant bacteria has limited their use and resulted in the need for novel aminoglycosides. Our group has synthesized two libraries of aminoglycosides: pyranmycin and kanamycin analogs, utilizing the glycodiversification concept. Several of them show promising activity against both susceptible and resistant strains of E. coli. The structure activity relationship of these compounds further provides information for the future designs of aminoglycoside.
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