Effects of N-alkylation and N-acylation on tobramycin activity.

Sicsic, Sames; Bigot, J. F. Le; Vincent, Christian; Cerceau, Claude

doi:10.7164/antibiotics.35.574

Cited by 7 publications

(8 citation statements)

References 11 publications

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“…The final deprotected N-AHB and N-glycinyl analogues (1b, 1d, 2b, and 2d) were obtained by catalytic hydrogenation of the azide and Cbz protecting groups with no additional purification required after the deprotection step in yields ranging from 82-95%. The position of acylation, purity, and structure identification were confirmed by 1 H, 13 C, 1D-TOCSY, DEPT, and HMQC NMR as well as HR-ESI-MS (Figs. S1-S12, ESI †).…”

Section: Resultsmentioning

confidence: 88%

“…Compounds were purified by SiO 2 flash chromatography (Merck, Kieselgel 60). 1 H NMR spectra (including DEPT, 2D-COSY, 1D-TOCSY, HMQC, and HMBC) and 13 C NMR spectra were recorded on Bruker Avance TM 400 and 500 spectrometers. Low-resolution electron spray ionization (LR-ESI) mass spectra were measured on a Waters 3100 mass detector.…”

Section: Bacterial Strains Plasmids Materials and Instrumentationmentioning

confidence: 99%

“…Indeed, 6¢-N-acetyl tobramycin has been shown to maintain significant antibacterial activity, indicating that while still deactivating, 6¢-N-acylation of this aminoglycoside scaffold has a more limited effect on the drug efficacy. 13 In the case of the 4,5-substituted 2deoxystreptamine paromomycin that lacks a 6¢-amine (Scheme 1), the 6¢¢¢-amine has no specific interactions with the target rRNA thereby making it an attractive position for the development of 6¢¢¢-N-acylated paromomycin analogues resistant to chemoenzymatic inactivation by AAC(6¢) enzymes. 14 We therefore suggested that replacing the 6¢-or 6¢¢¢-amine groups of tobramycin and paromomycin, respectively, with acyl groups such as those found on other naturally occurring as well as semi-synthetic Nacylated aminoglycosides may prove to be a useful strategy to overcome AAC(6¢)-based bacterial resistance to aminoglycosides while still maintaining good antibacterial activity.…”

Section: Introductionmentioning

confidence: 99%

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Assessment of 6′- and 6′′′-N-acylation of aminoglycosides as a strategy to overcome bacterial resistance

et al. 2011

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Amongst the many synthetic aminoglycoside analogues that were developed to regain the efficacy of this class of antibiotics against resistant bacterial strains, the 1-N-acylated analogues are the most clinically used. In this study we demonstrate that 6'-N-acylation of the clinically used compound tobramycin and 6'''-N-acylation of paromomycin result in derivatives resistant to deactivation by 6'-aminoglycoside acetyltransferase (AAC(6')) which is widely found in aminoglycoside resistant bacteria. When tested against AAC(6')- or AAC(3)-expressing bacteria as well as pathogenic bacterial strains, some of the analogues demonstrated improved antibacterial activity compared to their parent antibiotics. Improvement of the biological performance of the N-acylated analogues was found to be highly dependent on the specific aminoglycoside and acyl group. Our study indicates that as for 1-N-acylation, 6'- and 6'''-N-acylation of aminoglycosides offer an additional promising direction in the search for aminoglycosides capable of overcoming infections by resistant bacteria.

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Section: Resultsmentioning

confidence: 88%

Section: Bacterial Strains Plasmids Materials and Instrumentationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Assessment of 6′- and 6′′′-N-acylation of aminoglycosides as a strategy to overcome bacterial resistance

et al. 2011

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“…The more critical nature of the contacts made by the 3NH 2 than the 2’NH 2 is also supported by the MIC of tobramycin and 2’-Ac and 3-Ac tobramycin 34. In E. coli strains that lack resistance-causing enzymes, tobramycin has an MIC of 0.5 μg/mL whereas the MICs for 2’-Ac tobramycin and 3-Ac tobramycin are 32 and 256 μg/mL respectively.…”

Section: Discussionmentioning

confidence: 88%

Studying aminoglycoside modification by the acetyltransferase class of resistance-causing enzymes via microarray

Barrett¹,

Pushechnikov²,

Wu³

et al. 2008

Carbohydrate Research

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Aminoglycosides are broad-spectrum antibacterials to which some bacteria have acquired resistance. The most common mode of resistance to aminoglycosides is enzymatic modification of the drug by different classes of enzymes including acetyltransferases (AAC's). Thus, the modification of aminoglycosides by AAC(2') from Mycobacterium tuberculosis and AAC(3) from Escherichia coli was studied using aminoglycoside microarrays. Results show that both enzymes modify their substrates displayed on an array surface in a manner that mimics their relative levels of modification in solution. Because aminoglycosides that are modified by resistance-causing enzymes have reduced affinities for binding their therapeutic target, the bacterial rRNA aminoacyl-tRNA site (A-site), arrays were probed for binding to a fluorescently labeled oligonucleotide mimic of the A-site after modification. A decrease in binding was observed when aminoglycosides were modified by AAC (3). In contrast, a decrease in binding of the A-site is not observed when aminoglycosides are modified by AAC(2'). Interestingly, these effects mirror the biological functions of these enzymes: the AAC (3) used in this study is known to confer aminoglycoside resistance while the AAC(2') is chromosomally encoded and unlikely to play a role in resistance. These studies lay a direct foundation for studying resistance to aminoglycosides and can also have more broad applications in identifying and studying non-aminoglycoside carbohydrates or proteins as substrates for acetyltransferase enzymes.

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“…It is unique in that it leads to a strong stimulation of biosynthesis at concentrations higher than 70 puM. Moreover, acetylfortimicin is totally unable to inhibit polyphenylalanine synthesis, whereas tobramycin does not lose this ability after acetylation (25). As to its effect on ribosome dissociation, fortimicin differs from both streptomycin and tobramycin, but remains similar to gentamicin.…”

Section: Discussionmentioning

confidence: 99%

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

Moreau¹,

Jaxel²

1984

Antimicrob Agents Chemother

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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.

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Effects of N-alkylation and N-acylation on tobramycin activity.

Cited by 7 publications

References 11 publications

Assessment of 6′- and 6′′′-N-acylation of aminoglycosides as a strategy to overcome bacterial resistance

Assessment of 6′- and 6′′′-N-acylation of aminoglycosides as a strategy to overcome bacterial resistance

Studying aminoglycoside modification by the acetyltransferase class of resistance-causing enzymes via microarray

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

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