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Alexander S Mankin - One of the best experts on this subject based on the ideXlab platform.
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Resistance to Ketolide antibiotics by coordinated expression of rRNA methyltransferases in a bacterial producer of natural Ketolides.
Proceedings of the National Academy of Sciences, 2015Co-Authors: Mashal M. Almutairi, Stephen Douthwaite, Sung Ryeol Park, Simon Rose, Douglas A. Hansen, Nora Vázquez-laslop, David H. Sherman, Alexander S MankinAbstract:Ketolides are promising new antimicrobials effective against a broad range of Gram-positive pathogens, in part because of the low propensity of these drugs to trigger the expression of resistance genes. A natural Ketolide pikromycin and a related compound methymycin are produced by Streptomyces venezuelae strain ATCC 15439. The producer avoids the inhibitory effects of its own antibiotics by expressing two paralogous rRNA methylase genes pikR1 and pikR2 with seemingly redundant functions. We show here that the PikR1 and PikR2 enzymes mono- and dimethylate, respectively, the N6 amino group in 23S rRNA nucleotide A2058. PikR1 monomethylase is constitutively expressed; it confers low resistance at low fitness cost and is required for Ketolide-induced activation of pikR2 to attain high-level resistance. The regulatory mechanism controlling pikR2 expression has been evolutionary optimized for preferential activation by Ketolide antibiotics. The resistance genes and the induction mechanism remain fully functional when transferred to heterologous bacterial hosts. The anticipated wide use of Ketolide antibiotics could promote horizontal transfer of these highly efficient resistance genes to pathogens. Taken together, these findings emphasized the need for surveillance of pikR1/pikR2-based bacterial resistance and the preemptive development of drugs that can remain effective against the Ketolide-specific resistance mechanism.
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Induction of erm(C) Expression by Noninducing Antibiotics
Antimicrobial Agents and Chemotherapy, 2008Co-Authors: Marne Bailey, Tobin Chettiath, Alexander S MankinAbstract:Ketolides, which represent the newest macrolide antibiotics, are generally perceived to be noninducers of inducible erm genes. In the study described in this paper we investigated the effects of several macrolide and Ketolide compounds on the expression of the inducible erm(C) gene by Escherichia coli cells. Exposure to 14-member-ring macrolide drugs and to azithromycin led to a rapid and pronounced increase in the extent of dimethylation of Erm(C) target residue A2058 in 23S rRNA. When cells were incubated with subinhibitory concentrations of Ketolides, the extent of A2058 dimethylation was also increased, albeit to a lower level and with kinetics slower than those observed with macrolides. The induction of erm(C) expression by Ketolides was further confirmed by using a reporter construct which allows the colorimetric detection of induction in a disc diffusion assay. Most of the Ketolides tested, including the clinically relevant compounds telithromycin and cethromycin, were able to induce the reporter expression, even though the induction occurred within a more narrow range of concentrations compared to the concentration range at which induction was achieved with the inducing macrolide antibiotics. No induction of the reporter expression was observed with 16-member-ring macrolide antibiotics or with a control drug, chloramphenicol. The deletion of three codons of the erm(C) leader peptide eliminated macrolide-dependent induction but left Ketolide-dependent induction unchanged. We conclude that Ketolides are generally capable of inducing erm genes. The narrow range of Ketolide inducing concentrations, coupled with the slow rate of induction and the lower steady-state level of ribosome methylation, may mask this effect in MIC assays.
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binding site of macrolide antibiotics on the ribosome new resistance mutation identifies a specific interaction of Ketolides with rrna
Journal of Bacteriology, 2001Co-Authors: Georgina Garzaramos, Liqun Xiong, Ping Zhong, Alexander S MankinAbstract:Macrolides represent a clinically important class of antibiotics that block protein synthesis by interacting with the large ribosomal subunit. The macrolide binding site is composed primarily of rRNA. However, the mode of interaction of macrolides with rRNA and the exact location of the drug binding site have yet to be described. A new class of macrolide antibiotics, known as Ketolides, show improved activity against organisms that have developed resistance to previously used macrolides. The biochemical reasons for increased potency of Ketolides remain unknown. Here we describe the first mutation that confers resistance to Ketolide antibiotics while leaving cells sensitive to other types of macrolides. A transition of U to C at position 2609 of 23S rRNA rendered E. coli cells resistant to two different types of Ketolides, telithromycin and ABT-773, but increased slightly the sensitivity to erythromycin, azithromycin, and a cladinose-containing derivative of telithromycin. Ribosomes isolated from the mutant cells had reduced affinity for Ketolides, while their affinity for erythromycin was not diminished. Possible direct interaction of Ketolides with position 2609 in 23S rRNA was further confirmed by RNA footprinting. The newly isolated Ketolide-resistance mutation, as well as 23S rRNA positions shown previously to be involved in interaction with macrolide antibiotics, have been modeled in the crystallographic structure of the large ribosomal subunit. The location of the macrolide binding site in the nascent peptide exit tunnel at some distance from the peptidyl transferase center agrees with the proposed model of macrolide inhibitory action and explains the dominant nature of macrolide resistance mutations. Spatial separation of the rRNA residues involved in universal contacts with macrolides from those believed to participate in structure-specific interactions with Ketolides provides the structural basis for the improved activity of the broader spectrum group of macrolide antibiotics.
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a Ketolide resistance mutation in domain ii of 23s rrna reveals the proximity of hairpin 35 to the peptidyl transferase centre
Molecular Microbiology, 1999Co-Authors: Liqun Xiong, Sunita Shah, Pascale Mauvais, Alexander S MankinAbstract:: Ketolides represent a new generation of macrolide antibiotics. In order to identify the Ketolide-binding site on the ribosome, a library of Escherichia coli clones, transformed with a plasmid carrying randomly mutagenized rRNA operon, was screened for mutants exhibiting resistance to the Ketolide HMR3647. Sequencing of the plasmid isolated from one of the resistant clones and fragment exchange demonstrated that a single U754A mutation in hairpin 35 of domain II of the E. coli 23S rRNA was sufficient to confer resistance to low concentrations of the Ketolide. The same mutation also conferred erythromycin resistance. Both the Ketolide and erythromycin protected A2058 and A2059 in domain V of 23S rRNA from modification with dimethyl sulphate, whereas, in domain II, the Ketolide protected, while erythromycin enhanced, modification of A752 in the loop of the hairpin 35. Thus, mutational and footprinting results strongly suggest that the hairpin 35 constitutes part of the macrolide binding site on the ribosome. Strong interaction of Ketolides with the hairpin 35 in 23S rRNA may account for the high activity of Ketolides against erythromycin-resistant strains containing rRNA methylated at A2058. The existence of macrolide resistance mutations in the central loop of domain V and in hairpin 35 in domain II together with antibiotic footprinting data suggest that these rRNA segments may be in close proximity in the ribosome and that hairpin 35 may be a constituent part of the ribosomal peptidyl transferase centre.
D Felmingham - One of the best experts on this subject based on the ideXlab platform.
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evolving resistance patterns in community acquired respiratory tract pathogens first results from the protekt global surveillance study prospective resistant organism tracking and epidemiology for the Ketolide telithromycin
Journal of Infection, 2002Co-Authors: D FelminghamAbstract:In recent years, antibacterial resistance among respiratory pathogens implicated in community-acquired respiratory tract infections (RTIs) has spread worldwide at an alarming rate. Thus, there is a pressing need for new antibacterials that retain activity against resistant organisms, have a low potential to select for resistance and do not induce cross-resistance. Telithromycin is the first of a new class of antibacterials - the Ketolides - that have been designed specifically to overcome resistance among respiratory tract pathogens. This paper presents the first results of the PROTEKT study (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin), a worldwide surveillance study initiated to chart the prevalence of important resistance phenotypes and genotypes and the comparative activity of telithromycin against such strains. Analysis of over 7,000 bacterial isolates by April 2001 has confirmed the notable prevalence of strains resistant to commonly prescribed RTI antibacterials for all the pathogens studied. Telithromycin demonstrates high activity against isolates of Streptococcus pneumoniae, irrespective of penicillin G, macrolide or fluoroquinolone resistance. Telithromycin is also highly active against other respiratory tract pathogens, including Streptococcus pyogenes and beta-lactamase-producing strains of Haemophilus influenzae and Moraxella catarrhalis. These data justify the assertion that telithromycin is a promising new candidate for the empirical treatment of community-acquired RTIs, particularly in the face of increasing antibacterial resistance.
Solange Gouin Dambrieres - One of the best experts on this subject based on the ideXlab platform.
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synthesis and antibacterial activity of hmr 3647 a new Ketolide highly potent against erythromycin resistant and susceptible pathogens
Bioorganic & Medicinal Chemistry Letters, 1999Co-Authors: Alexis Denis, Jeanmichel Auger, Yannick Benedetti, Arlette Dussarat, Francois Bretin, Claude Fromentin, Alain Bonnefoy, Constantin Agouridas, Jean-francois Chantot, Solange Gouin DambrieresAbstract:Abstract In the search for new Ketolides with improved activities against erythromycin-resistant S. pneumoniae and H. influenzae we synthesized a new 11,12 carbamate Ketolide substituted by an imidazo-pyridyl side chain: HMR 3647. This compound demonstrated a potent activity against erythromycin susceptible and resistant pathogens, including penicillin G/erythromycin A-resistant S. pneumoniae and H. influenzae. In vivo , HMR 3647 displayed good pharmacokinetic parameters (Cmax = 2.9 μg/ml, bioavailability=49%, AUC 0–8 = 17.2 μg.h/l, t 1 2 =1 h) and was shown to have a high therapeutic efficacy in mice infected by various respiratory pathogens, including multi-resistant S. pneumoniae and Gram negative bacteria such as H. influenzae . HMR 3647 appears to be a very promising agent for the treatment of respiratory infections and is currently in clinical trials.
Birgit Heinisch - One of the best experts on this subject based on the ideXlab platform.
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Ketolides — The Modern Relatives of Macrolides
Clinical Pharmacokinetics, 2009Co-Authors: Markus Zeitlinger, Claudia Christina Wagner, Birgit HeinischAbstract:As with other widely used antibacterials, the abundant use of macrolides for management of ambulant infections has promoted emergence of resistance against them. Ketolides are structurally related to macrolides and were developed to overcome macrolide resistance, while sharing pharmacodynamic and pharmacokinetic characteristics. However, until now, there have been no comprehensive reviews of the comparative pharmacokinetics of macrolides and Ketolides. This article reviews the pharmacokinetic parameters in plasma and relevant tissues of telithromycin, the only approved Ketolide, and cethromycin, which is currently in phase III of clinical development. For comparison, the 14-membered macrolides clarithromycin and roxithromycin and the 15-membered azalide azithromycin were chosen as representatives of their class. While telithromycin achieves higher plasma concentrations than cethromycin, both antimicrobials display comparable elimination half-lives and clearance. Repeated dosing rarely influences the pharmacokinetic parameters of Ketolides. Despite substantially higher maximum plasma concentrations and area under the plasma concentration-time curve (AUC) values of telithromycin, the higher antimicrobial activity of cethromycin leads to similar ratios between the AUC from 0 to 24 hours (AUC_24) and the minimum inhibitory concentration (MIC) for relevant pathogens, suggesting comparable antimicrobial activity of both antimicrobials in plasma. Although telithromycin and cethromycin show plasma-protein binding of 90%, they have excellent tissue penetration, as indicated by volumes of distribution of about 500 L and high intracellular concentrations. Besides enhancing killing of intracellular pathogens, the high concentrations of macrolides, azalides and Ketolides in leukocytes have been associated with increased delivery of the antimicrobial agent to the site of infection. Although telithromycin has been shown to accumulate in alveolar macrophages and epithelial lining fluid by 380- and 15-fold, respectively (relative to plasma concentrations), its concentration in the interstitium of soft tissues is comparable to the free fraction in plasma. Thus the pharmacokinetics of Ketolides may help to explain their good activity against a wide range of respiratory tract infections, although pharmacokinetic/pharmacodynamic calculations based on plasma pharmacokinetics would indicate only minor activity against pathogens except streptococci. In contrast, AUC_24/MIC ratios achieved in soft tissue may be considered insufficient to kill extracellular pathogens causing soft tissue infections, except for Streptococcus pyogenes . Although Ketolides and macrolides share relevant pharmacokinetic properties, the pharmacokinetics of both antimicrobial classes are not considered interchangeable. With a volume of distribution similar to that of azithromycin but plasma concentrations and an elimination half-life reflecting those of clarithromycin, the pharmacokinetics of Ketolides may be considered ‘intermediate’ between those of macrolides and azalides. Thus the pharmacokinetics of Ketolides can be considered similar but not identical to those of macrolides.
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Ketolides -The Modern Relatives of Macrolides : The Pharmacokinetic Perspective
Clinical Pharmacokinetics, 2009Co-Authors: Markus Zeitlinger, Claudia Christina Wagner, Birgit HeinischAbstract:As with other widely used antibacterials, the abundant use of macrolides for management of ambulant infections has promoted emergence of resistance against them. Ketolides are structurally related to macrolides and were developed to overcome macrolide resistance, while sharing pharmacodynamic and pharmacokinetic characteristics. However, until now, there have been no comprehensive reviews of the comparative pharmacokinetics of macrolides and Ketolides.
Alexis Denis - One of the best experts on this subject based on the ideXlab platform.
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Synthesis of 9-oxime-11,12-carbamate Ketolides through a novel N-deamination reaction of 11,12-hydrazonocarbamate Ketolide.
Bioorganic & Medicinal Chemistry, 2003Co-Authors: Alexis Denis, Francois Bretin, Jean-marie Pejac, Alain BonnefoyAbstract:A series of 9-oxime-11,12-carbamate Ketolides was synthesized for the first time through a key 11,12-hydrazonocarbamate intermediate that was first oximated and further deaminated to give the corresponding carbamate. The N-N bond cleavage was achieved through an original new reaction using glycoaldehyde dimer as deaminating reagent. The new compounds synthesized were shown to display improved antibacterial activities against Streptococcus pneumoniae and S. pyogenes resistant to erythromycin.
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Novel N-demethylation of Ketolide: application to the solution phase parallel synthesis of N-desosaminyl-substituted Ketolides using ion exchange resins
Tetrahedron Letters, 2002Co-Authors: Alexis Denis, Christelle C. RenouAbstract:A series of N-desosaminyl-substituted Ketolides was synthesized in parallel by reductive amination of various aldehydes by a N-desmethyl-Ketolide scaffold followed by a solid phase extraction protocol using ion exchange resins. In addition, we have demonstrated that diethyl azodicarboxylate (DEAD) can be used efficiently as a N-demethylating reagent to access to N-desmethyl-Ketolides.
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β keto ester chemistry and Ketolides synthesis and antibacterial activity of 2 halogeno 2 methyl and 2 3 enol ether Ketolides
Bioorganic & Medicinal Chemistry Letters, 2000Co-Authors: Alexis Denis, Francois Bretin, Claude Fromentin, Alain Bonnefoy, Constantin Agouridas, A Bonnet, G PiltanAbstract:Abstract The effect of 2,3 modifications on the antibacterial activity of Ketolides was evaluated by introducing substituents in position 2 and converting the C-1, C-2, C-3 β-keto-ester into stable 2,3 enol-ether or 2,3 anhydro derivatives. Introduction of a fluorine in C-2 is beneficial with regard to the overall antibacterial spectrum whereas the enol-ether and 2,3 unsaturated compounds, as well as the bulky gem dimethyl or 2-chloro derivatives, are less active particularly against erythromycin resistant strains. A 2-fluoro Ketolide derivative demonstrates good antibacterial activity and in vivo efficacy against multi-resistant Streptococcus pneumoniae . Compared to azithromycin against Haemophilus influenzae , this compound is equivalent in vitro and slightly more active in vivo. These results demonstrate that within the Ketolide class, to retain good antibacterial activity, position 2 needs to remain tetrahedral and tolerates only very small substituents such as fluorine.
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synthesis and antibacterial activity of hmr 3647 a new Ketolide highly potent against erythromycin resistant and susceptible pathogens
Bioorganic & Medicinal Chemistry Letters, 1999Co-Authors: Alexis Denis, Jeanmichel Auger, Yannick Benedetti, Arlette Dussarat, Francois Bretin, Claude Fromentin, Alain Bonnefoy, Constantin Agouridas, Jean-francois Chantot, Solange Gouin DambrieresAbstract:Abstract In the search for new Ketolides with improved activities against erythromycin-resistant S. pneumoniae and H. influenzae we synthesized a new 11,12 carbamate Ketolide substituted by an imidazo-pyridyl side chain: HMR 3647. This compound demonstrated a potent activity against erythromycin susceptible and resistant pathogens, including penicillin G/erythromycin A-resistant S. pneumoniae and H. influenzae. In vivo , HMR 3647 displayed good pharmacokinetic parameters (Cmax = 2.9 μg/ml, bioavailability=49%, AUC 0–8 = 17.2 μg.h/l, t 1 2 =1 h) and was shown to have a high therapeutic efficacy in mice infected by various respiratory pathogens, including multi-resistant S. pneumoniae and Gram negative bacteria such as H. influenzae . HMR 3647 appears to be a very promising agent for the treatment of respiratory infections and is currently in clinical trials.
