Novel Inhibitors of Erm Methyltransferases from NMR and Parallel Synthesis

Hajduk, Philip J.; Dinges, Jürgen; Schkeryantz, Jeffrey M.; Janowick, David A.; Kaminski, Michele; Tufano, Michael D.; Augeri, David J.; Petros, Andrew M.; Nienaber, V.; Zhong, Ping; Hammond, Rachel; Coen, Michael; Beutel, Bruce A.; Katz, Leonard; Fesik, Stephen W.

doi:10.1021/jm990293a

Cited by 123 publications

(67 citation statements)

References 23 publications

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“…This finding is related to the different interaction points involved in the interaction of tylosin with 23S rRNA, as mentioned previously. Some groups have attempted to design methylase inhibitors able to restore the macrolide activity of bacterial isolates carrying these genes (Hajduk et al, 1999), but no molecule is currently under development for therapeutic use in humans.…”

Section: Methylationmentioning

confidence: 99%

Macrolide resistance mechanisms inEnterobacteriaceae: Focus on azithromycin

Gomes

Martínez-Puchol

Palma

et al. 2016

Critical Reviews in Microbiology

119

120

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Section: Methylationmentioning

confidence: 99%

Macrolide resistance mechanisms inEnterobacteriaceae: Focus on azithromycin

Gomes

Martínez-Puchol

Palma

et al. 2016

Critical Reviews in Microbiology

119

120

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“…This strategy can be used when resistance involves antibiotic-inactivating enzymes, and it has been validated with the successful use of β-lactamase inhibitors [17]. A similar approach can be used for target-modifying enzymes [18] and for efflux systems [19].…”

Section: Introductionmentioning

confidence: 99%

Fluoroquinolone resistant mechanisms in methicillin-resistant Staphylococcus aureus clinical isolates in Cairo, Egypt

Hashem

Yassin

Zedan

et al. 2013

J Infect Dev Ctries

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Introduction: Methicillin-resistant Staphylococcus aureus (MRSA) is a persistent problem in community and health care settings. Fluoroquinolones are among the drugs of choice used to treat MRSA infections. This study aims to identify different mechanisms of fluoroquinolne resistance in local MRSA random sampling isolates in Cairo, Egypt. Methodology: A total of 94 clinical isolates of S. aureus were collected from two major University hospitals in Cairo. Identification was confirmed by appropriate morphological, cultural, and biochemical tests. The antibiotic susceptibility pattern was determined for all isolates. The possible involvement of efflux pumps in mediating fluoroquinolone resistance as well as changes in the quinolone resistance determining region (QRDR) of gyrA and gyrB genes were investigated Results: A total of 45 isolates were found to be MRSA, among which 26 isolates were found to be fluoroquinolone-resistant. The MIC values of the tested fluoroquinolones in the presence of the efflux pump inhibitors omeprazole and piperine were reduced. Measuring the uptake of ciprofloxacin upon the addition of the efflux pump inhibitor omeprazole, an increased level of accumulation was observed. Non-synonymous and silent mutations were detected in the QRDR of gyrA and gyrB genes. Conclusions: These results shed light on some of the resistance patterns of MRSA strains isolated from local health care settings in Cairo, Egypt. The resistance of these MRSA towards fluoroquinolones does not depend only on mutation in target genes; other mechanisms of resistance such as the permeability effect, efflux pumps and decreased availability of quinolones at the target site can also be involved.

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“…Recent studies have reported on several potential Erm in- on May 11, 2018 by guest http://aac.asm.org/ hibitors whose actions are based on the ability of the end product of the methylation reaction, S-adenosyl-L-homocysteine, to inhibit the methylation reaction (10,11). These potential inhibitors bind to the active site of the Erm protein, thereby competing with the substrate of the methylation reaction, SAM.…”

Section: Discussionmentioning

confidence: 99%

Identification of Essential Residues in the Erm(B) rRNA Methyltransferase ofClostridium perfringens

Farrow

Lyras

Polekhina

et al. 2002

Antimicrob Agents Chemother

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Macrolide-lincosamide-streptogramin B resistance is widespread, with the determinants encoding resistance to antibiotics such as erythromycin being detected in many bacterial pathogens. Resistance is most commonly mediated by the production of an Erm protein, a 23S rRNA methyltransferase. We have undertaken a mutational analysis of the Erm(B) protein from Clostridium perfringens with the objective of developing a greater understanding of the mechanism of action of this protein. A recombinant plasmid that carried the erm(B) gene was mutated by either in vitro hydroxylamine mutagenesis or passage through the mutator strain XL1-Red. Twenty-eight independently derived mutants were identified, nine of which had single point mutations in the erm(B) gene. These mutants produced stable but nonfunctional Erm(B) proteins, and all had amino acid changes within conserved methyltransferase motifs that were important for either substrate binding or catalysis. Modeling of the C. perfringens Erm(B) protein confirmed that the point mutations all involved residues important for the structure and/or function of this rRNA methyltransferase. These regions of the protein therefore represent potential targets for the rational development of methyltransferase inhibitors.Macrolide, lincosamide, and streptogramin B (MLS) antibiotics are a diverse group of antibacterial agents that are chemically distinct but that have similar modes of action. They act at the early stages of protein synthesis by blocking the growth of the nascent peptide chain (1), which then presumably causes the premature dissociation of the peptidyl-tRNA molecule from the ribosome (22). These antibiotics include erythromycin, clindamycin, and lincomycin and are active against various bacteria, including gram-positive cocci and rods and gramnegative cocci.Four mechanisms of bacterial resistance to MLS antibiotics have been detected; they involve enzymatic modification of the antibiotic, active efflux from the bacterial cell, mutation of the ribosomal target site, or, most commonly, enzyme-mediated chemical alteration of the rRNA target (18,19,33). The last mechanism is mediated by the synthesis of a 23S rRNA methyltransferase, which is responsible for the N 6 -dimethylation of a specific adenine residue in the 23S rRNA molecule (17).Methyltransferases are enzymes that methylate a wide variety of substrates; they use S-adenosyl-L-methionine (SAM) as the universal methyl donor and release S-adenosyl-L-homocysteine as the reaction product (4). Comparative analysis of over 40 DNA amino-methyltransferases (21) revealed the presence of nine conserved sequence motifs that are important in target sequence specificity, catalysis, and SAM binding (Fig. 1). Motif I is highly conserved and forms a secondary structure known as the G loop which binds to the methionine moiety of SAM.Motifs II and III are less conserved, with motif II containing a negatively charged amino acid that interacts with the ribose hydroxyls of SAM and a bulky hydrophobic side chain that makes contact with the...

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Novel Inhibitors of Erm Methyltransferases from NMR and Parallel Synthesis

Cited by 123 publications

References 23 publications

Macrolide resistance mechanisms inEnterobacteriaceae: Focus on azithromycin

Macrolide resistance mechanisms inEnterobacteriaceae: Focus on azithromycin

Fluoroquinolone resistant mechanisms in methicillin-resistant Staphylococcus aureus clinical isolates in Cairo, Egypt

Identification of Essential Residues in the Erm(B) rRNA Methyltransferase ofClostridium perfringens

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