Cross-linking in the Living Cell Locates the Site of Action of Oxazolidinone Antibiotics

Colca, Jerry R.; McDonald, William Graham; Waldon, Daniel J.; Thomasco, Lisa M.; Gadwood, Robert C.; Lund, Eric T.; Cavey, Gregory S.; Mathews, W R; Adams, Luke A.; Cecil, Eric T.; Pearson, J.; Bock, Jeffrey H.; Mott, John E.; Shinabarger, Dean L.; Xiong, Liqun; Mankin, Alexander S.

doi:10.1074/jbc.m302109200

Cited by 142 publications

(99 citation statements)

References 58 publications

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“…In contrast, recent studies using an elegant in vivo cross-linking approach revealed the PTC as the bone fide drug target (12,13). These latter studies are consistent with the observation that drug resistance in both archaea and bacteria arises through mutation of nucleotides located within the PTC [ Fig.…”

supporting

confidence: 75%

“…S5b) (37). In this regard, we note however that a ⌬lepA strain has an identical IC 50 for oxazolidinones as the wild-type strain (12), suggesting that the binding of LepA is a consequence, rather than a cause, of the functional state induced by the oxazolidinones.…”

Section: Discussionmentioning

confidence: 76%

“…also to the ribosomal elongation factor LepA (12,13). LepA is a translational GTPase that binds to POST state ribosomes inducing a back-translocation to the PRE state (37).…”

Section: Discussionmentioning

confidence: 99%

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The oxazolidinone antibiotics perturb the ribosomal peptidyl-transferase center and effect tRNA positioning

Wilson

Schluenzen

Harms

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

270

256

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The oxazolidinones represent the first new class of antibiotics to enter into clinical usage within the past 30 years, but their binding site and mechanism of action has not been fully characterized. We have determined the crystal structure of the oxazolidinone linezolid bound to the Deinococcus radiodurans 50S ribosomal subunit. Linezolid binds in the A site pocket at the peptidyltransferase center of the ribosome overlapping the aminoacyl moiety of an A-site bound tRNA as well as many clinically important antibiotics. Binding of linezolid stabilizes a distinct conformation of the universally conserved 23S rRNA nucleotide U2585 that would be nonproductive for peptide bond formation. In conjunction with available biochemical data, we present a model whereby oxazolidinones impart their inhibitory effect by perturbing the correct positioning of tRNAs on the ribosome.

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supporting

confidence: 75%

Section: Discussionmentioning

confidence: 76%

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The oxazolidinone antibiotics perturb the ribosomal peptidyl-transferase center and effect tRNA positioning

Wilson

Schluenzen

Harms

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

270

256

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“…Binding of linezolid to this area was subsequently supported by other mutagenesis studies but could not be verified by antibiotic footprinting, a technique that has been used successfully to localize ribosomal binding sites for other antibiotics. Cross-linking studies with linezolid derivatives also pointed to a location at the PTC (12,46). In 2008, this site was confirmed by crystal structures of linezolid bound to the 50S ribosomal subunit from the archaeon Haloarcula marismortui (36) and from the bacterium Deinococcus radiodurans (95).…”

Section: The Linezolid Binding Site On the Ribosomementioning

confidence: 83%

Resistance to Linezolid Caused by Modifications at Its Binding Site on the Ribosome

Long

Vester

2012

Antimicrob Agents Chemother

303

195

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Linezolid is an oxazolidinone antibiotic in clinical use for the treatment of serious infections of resistant Gram-positive bacteria. It inhibits protein synthesis by binding to the peptidyl transferase center on the ribosome. Almost all known resistance mechanisms involve small alterations to the linezolid binding site, so this review will therefore focus on the various changes that can adversely affect drug binding and confer resistance. High-resolution structures of linezolid bound to the 50S ribosomal subunit show that it binds in a deep cleft that is surrounded by 23S rRNA nucleotides. Mutation of 23S rRNA has for some time been established as a linezolid resistance mechanism. Although ribosomal proteins L3 and L4 are located further away from the bound drug, mutations in specific regions of these proteins are increasingly being associated with linezolid resistance. However, very little evidence has been presented to confirm this. Furthermore, recent findings on the Cfr methyltransferase underscore the modification of 23S rRNA as a highly effective and transferable form of linezolid resistance. On a positive note, detailed knowledge of the linezolid binding site has facilitated the design of a new generation of oxazolidinones that show improved properties against the known resistance mechanisms. LINEZOLID

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“…[2][3][4][5][6] With the increase in resistance of bacteria to antibiotic treatment, attention was given on developing novel approaches to antimicrobial therapy. [7][8][9][10][11][12][13] We have previously reported the significant antifungal activity of a series of sulfonamide-1,2,4-triazole derivatives against a series of micromycetes, compared to the commercial fungicide bifonazole. These compounds have also shown a comparable bactericidal effect to that of streptomycin but better activity than chlorampenicol respectively against various bacteria.…”

mentioning

confidence: 99%

Sulfonamide-1,2,4-thiadiazole Derivatives as Antifungal and Antibacterial Agents: Synthesis, Biological Evaluation, Lipophilicity, and Conformational Studies

et al. 2010

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Bacterial infections have increased dramatically in recent years. Bacteria have been the cause of some of the most deadly diseases and widespread epidemics in human civilization.1) Moreover, the widespread use and misuse of antibiotics has caused bacterial resistance. Some of these resistant strains, such as vancomycin-resistant enterococci (VRE) and multidrug resistant Staphylococcus aureus (MRSA), are capable of surviving the effects of most, if not all, antibiotics currently in use. [2][3][4][5][6] With the increase in resistance of bacteria to antibiotic treatment, attention was given on developing novel approaches to antimicrobial therapy. [7][8][9][10][11][12][13] We have previously reported the significant antifungal activity of a series of sulfonamide-1,2,4-triazole derivatives against a series of micromycetes, compared to the commercial fungicide bifonazole. These compounds have also shown a comparable bactericidal effect to that of streptomycin but better activity than chlorampenicol respectively against various bacteria. 14)Thiadiazoles belong to the wider category of imidazole and triazole synthetic antifungal drugs which are designed to inhibit the enzyme cytochrome P450 14a-demethylase and inhibit the conversion of lanosterol to ergosterol, which is required in fungal cell membrane synthesis.1,3,4-Thiadiazoles are known to possess antibacterial and antifungal properties similar to those of well known sulphonamide drugs.15) Thus, the 1,3,4-thiadiazoles exhibit a broad spectrum of biological activities possibly due to the presence of the toxophoric -N-C-S moiety.16) Prompted by these observations and in continuation of our search for bioactive molecules, we designed the synthesis of a series of novel sulfonamide-1,3,4-thiadiazoles, emphasizing, in particular, on the strategy of combining two chemically different but pharmacologically compatible molecules (the sulfonamide nucleus and the five member heterocycle) in one frame, in order to study their antibacterial and antifungal activities.Chemistry The synthetic pathway followed for the preparation of the title compounds was accomplished as shown in Chart 1.Starting from ethyl(2-chlorosulfonyl-4,5-dimethoxyphenyl)acetate (1) 17,18) by reaction with secondary aliphatic amines in anhydrous benzene the corresponding sulfonamides Results and DiscussionBiological Evaluation and Lipophilicity Studies The results of antibacterial and antifungal activity of compounds 5a-m against a panel of selected Gram positive, Gram negative bacteria and fungi are presented in Tables 1 and 2 in comparison with those of the reference drugs ampicillin and streptomycin, bifonazole and ketoconazole respectively.Results of antibacterial activity of compounds (Table 1) show that the minimum inhibitory concentration (MIC) of compounds varies in the range of 0.92-4.6ϫ10 Ϫ2 mmol/ml, while minimum bactericidal concentration (MBC) varies between 1. 75-9.20ϫ10 Ϫ2 mmol/ml. Compounds 5a, 5b, 5c and 5g showed the lowest antibacterial activity among the tested compounds with 5a being t...

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Cross-linking in the Living Cell Locates the Site of Action of Oxazolidinone Antibiotics

Cited by 142 publications

References 58 publications

The oxazolidinone antibiotics perturb the ribosomal peptidyl-transferase center and effect tRNA positioning

The oxazolidinone antibiotics perturb the ribosomal peptidyl-transferase center and effect tRNA positioning

Resistance to Linezolid Caused by Modifications at Its Binding Site on the Ribosome

Sulfonamide-1,2,4-thiadiazole Derivatives as Antifungal and Antibacterial Agents: Synthesis, Biological Evaluation, Lipophilicity, and Conformational Studies

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