The Experts below are selected from a list of 41568 Experts worldwide ranked by ideXlab platform
Robert A. Bonomo - One of the best experts on this subject based on the ideXlab platform.
-
Image_1_Acinetobacter nosocomialis: Defining the Role of Efflux Pumps in Resistance to Antimicrobial Therapy, Surface Motility, and Biofilm Formation.TIFF
2018Co-Authors: Daniel B. Knight, Robert A. Bonomo, Susan D Rudin, Philip N. RatherAbstract:Acinetobacter nosocomialis is a member of the Acinetobacter calcoaceticus-Acinetobacter baumannii (ACB) complex. Increasingly, reports are emerging of the pathogenic profile and multidrug resistance (MDR) phenotype of this species. To define novel therapies to overcome resistance, we queried the role of the major efflux pumps in A. nosocomialis strain M2 on antimicrobial susceptibility profiles. A. nosocomialis strains with the following mutations were engineered by allelic replacement; ΔadeB, ΔadeJ, and ΔadeB/adeJ. In these isogenic strains, we show that the ΔadeJ mutation increased susceptibility to beta-lactams, beta-lactam/Beta-Lactamase Inhibitors, chloramphenicol, monobactam, tigecycline, and trimethoprim. The ΔadeB mutation had a minor effect on resistance to certain beta-lactams, rifampicin and tigecycline. In addition, the ΔadeJ mutation resulted in a significant decrease in surface motility and a minor decrease in biofilm formation. Our results indicate that the efflux pump, AdeIJK, has additional roles outside of antibiotic resistance in A. nosocomialis.
-
Acinetobacter nosocomialis: Defining the Role of Efflux Pumps in Resistance to Antimicrobial Therapy, Surface Motility, and Biofilm Formation
Frontiers Media S.A., 2018Co-Authors: Daniel B. Knight, Robert A. Bonomo, Susan D Rudin, Philip N. RatherAbstract:Acinetobacter nosocomialis is a member of the Acinetobacter calcoaceticus-Acinetobacter baumannii (ACB) complex. Increasingly, reports are emerging of the pathogenic profile and multidrug resistance (MDR) phenotype of this species. To define novel therapies to overcome resistance, we queried the role of the major efflux pumps in A. nosocomialis strain M2 on antimicrobial susceptibility profiles. A. nosocomialis strains with the following mutations were engineered by allelic replacement; ΔadeB, ΔadeJ, and ΔadeB/adeJ. In these isogenic strains, we show that the ΔadeJ mutation increased susceptibility to beta-lactams, beta-lactam/Beta-Lactamase Inhibitors, chloramphenicol, monobactam, tigecycline, and trimethoprim. The ΔadeB mutation had a minor effect on resistance to certain beta-lactams, rifampicin and tigecycline. In addition, the ΔadeJ mutation resulted in a significant decrease in surface motility and a minor decrease in biofilm formation. Our results indicate that the efflux pump, AdeIJK, has additional roles outside of antibiotic resistance in A. nosocomialis
-
treatment options for infections caused by carbapenem resistant enterobacteriaceae can we apply precision medicine to antimicrobial chemotherapy
Expert Opinion on Pharmacotherapy, 2016Co-Authors: Federico Perez, Nadim El G Chakhtoura, Krisztina M Pappwallace, Brigid Wilson, Robert A. BonomoAbstract:ABSTRACTIntroduction: For the past three decades, carbapenems played a central role in our antibiotic armamentarium, trusted to effectively treat infections caused by drug-resistant bacteria. The utility of this class of antibiotics has been compromised by the emergence of resistance especially among Enterobacteriaceae.Areas covered: We review the current mainstays of pharmacotherapy against infections caused by carbapenem-resistant Enterobacteriaceae (CRE) including tigecycline, aminoglycosides, and rediscovered ‘old’ antibiotics such as fosfomycin and polymyxins, and discuss their efficacy and potential toxicity. We also summarize the contemporary clinical experience treating CRE infections with antibiotic combination therapy. Finally, we discuss ceftazidime/avibactam and imipenem/relebactam, containig a new generation of Beta-Lactamase Inhibitors, which may offer alternatives to treat CRE infections. We critically evaluate the published literature, identify relevant clinical trials and review documents...
-
three decades of beta lactamase Inhibitors
Clinical Microbiology Reviews, 2010Co-Authors: Sarah M Drawz, Robert A. BonomoAbstract:Since the introduction of penicillin, beta-lactam antibiotics have been the antimicrobial agents of choice. Unfortunately, the efficacy of these life-saving antibiotics is significantly threatened by bacterial Beta-Lactamases. Beta-Lactamases are now responsible for resistance to penicillins, extended-spectrum cephalosporins, monobactams, and carbapenems. In order to overcome Beta-Lactamase-mediated resistance, Beta-Lactamase Inhibitors (clavulanate, sulbactam, and tazobactam) were introduced into clinical practice. These Inhibitors greatly enhance the efficacy of their partner beta-lactams (amoxicillin, ampicillin, piperacillin, and ticarcillin) in the treatment of serious Enterobacteriaceae and penicillin-resistant staphylococcal infections. However, selective pressure from excess antibiotic use accelerated the emergence of resistance to beta-lactam-Beta-Lactamase inhibitor combinations. Furthermore, the prevalence of clinically relevant Beta-Lactamases from other classes that are resistant to inhibition is rapidly increasing. There is an urgent need for effective Inhibitors that can restore the activity of beta-lactams. Here, we review the catalytic mechanisms of each Beta-Lactamase class. We then discuss approaches for circumventing Beta-Lactamase-mediated resistance, including properties and characteristics of mechanism-based inactivators. We next highlight the mechanisms of action and salient clinical and microbiological features of Beta-Lactamase Inhibitors. We also emphasize their therapeutic applications. We close by focusing on novel compounds and the chemical features of these agents that may contribute to a "second generation" of Inhibitors. The goal for the next 3 decades will be to design Inhibitors that will be effective for more than a single class of Beta-Lactamases.
-
tazobactam forms a stoichiometric trans enamine intermediate in the e166a variant of shv 1 beta lactamase 1 63 a crystal structure
Biochemistry, 2004Co-Authors: Pius S Padayatti, Robert A. Bonomo, Marion S Helfand, Monica A Totir, Marianne P Carey, Andrea M Hujer, Paul R Carey, Focco Van Den AkkerAbstract:Many pathogenic bacteria develop antibiotic resistance by utilizing Beta-Lactamases to degrade penicillin-like antibiotics. A commonly prescribed mechanism-based inhibitor of Beta-Lactamases is tazobactam, which can function either irreversibly or in a transient manner. We have demonstrated previously that the reaction between tazobactam and a deacylation deficient variant of SHV-1 Beta-Lactamase, E166A, could be followed in single crystals using Raman microscopy [Helfand, M. S., et al. (2003) Biochemistry 42, 13386-13392]. The Raman data show that maximal populations of an enamine-like intermediate occur 20-30 min after "soaking in" has commenced. By flash-freezing crystals in this time frame, we were able to trap the enamine species. The resulting 1.63 A resolution crystal structure revealed tazobactam covalently bound in the trans-enamine intermediate state with close to 100% occupancy in the active site. The Raman data also indicated that tazobactam forms a larger population of enamine than sulbactam or clavulanic acid does and that tazobactam's intermediate is also the most long-lived. The crystal structure provides a rationale for this finding since only tazobactam is able to form favorable intra- and intermolecular interactions in the active site that stabilize this trans-enamine intermediate. These interactions involve both the sulfone and triazolyl groups that distinguish tazobactam from clavulanic acid and sulbactam, respectively. The observed stabilization of the transient intermediate of tazobactam is thought to contribute to tazobactam's superior in vitro and in vivo clinical efficacy. Understanding the structural details of differing inhibitor effectiveness can aid the design of improved mechanism-based Beta-Lactamase Inhibitors.
D Knowles - One of the best experts on this subject based on the ideXlab platform.
-
comparative activities of clavulanic acid sulbactam and tazobactam against clinically important beta lactamases
Antimicrobial Agents and Chemotherapy, 1994Co-Authors: David J Payne, R Cramp, D J Winstanley, D KnowlesAbstract:Clavulanic acid, sulbactam, and tazobactam are Inhibitors of a variety of plasmid-mediated Beta-Lactamases. However, inhibition data for these three Inhibitors with a wide range of different plasmid-mediated Beta-Lactamases have not yet been compared under the same experimental conditions. A number of groups have inferred that clavulanic acid inhibits extended-spectrum TEM and SHV Beta-Lactamases, but inhibition data have rarely been published. In this study, the 50% inhibitory concentrations of these three Beta-Lactamase Inhibitors for 35 plasmid-mediated Beta-Lactamases have been determined. Of these 35 Beta-Lactamases, 20 were extended-spectrum TEM- or SHV-derived Beta-Lactamases. The other 15 enzymes were conventional-spectrum Beta-Lactamases such as TEM-1 and SHV-1. Clavulanic acid was a more potent inhibitor than sulbactam for 32 of the 35 plasmid-mediated Beta-Lactamases tested. In particular, clavulanic acid was 60 and 580 times more potent than sulbactam against TEM-1 and SHV-1, respectively, currently the two most clinically prevalent gram-negative plasmid-mediated Beta-Lactamases. Statistical analysis of the data of the 50% inhibitory concentrations showed that clavulanic acid was 20 times more active overall than sulbactam against the conventional-spectrum enzymes. In addition, clavulanic acid was 14 times more potent than sulbactam at inhibiting the extended-spectrum enzymes. Tazobactam also showed significantly greater activity than sulbactam against the two groups of Beta-Lactamases. There were no significant differences between the overall activities of tazobactam and clavulanic acid against the extended-spectrum TEM and SHV enzymes and conventional-spectrum enzymes, although differences in their inhibition profiles were observed.
-
comparative activities of clavulanic acid sulbactam and tazobactam against clinically important beta lactamases
Antimicrobial Agents and Chemotherapy, 1994Co-Authors: David J Payne, R Cramp, D J Winstanley, D KnowlesAbstract:Clavulanic acid, sulbactam, and tazobactam are Inhibitors of a variety of plasmid-mediated Beta-Lactamases. However, inhibition data for these three Inhibitors with a wide range of different plasmid-mediated Beta-Lactamases have not yet been compared under the same experimental conditions. A number of groups have inferred that clavulanic acid inhibits extended-spectrum TEM and SHV Beta-Lactamases, but inhibition data have rarely been published. In this study, the 50% inhibitory concentrations of these three Beta-Lactamase Inhibitors for 35 plasmid-mediated Beta-Lactamases have been determined. Of these 35 Beta-Lactamases, 20 were extended-spectrum TEM- or SHV-derived Beta-Lactamases. The other 15 enzymes were conventional-spectrum Beta-Lactamases such as TEM-1 and SHV-1. Clavulanic acid was a more potent inhibitor than sulbactam for 32 of the 35 plasmid-mediated Beta-Lactamases tested. In particular, clavulanic acid was 60 and 580 times more potent than sulbactam against TEM-1 and SHV-1, respectively, currently the two most clinically prevalent gram-negative plasmid-mediated Beta-Lactamases. Statistical analysis of the data of the 50% inhibitory concentrations showed that clavulanic acid was 20 times more active overall than sulbactam against the conventional-spectrum enzymes. In addition, clavulanic acid was 14 times more potent than sulbactam at inhibiting the extended-spectrum enzymes. Tazobactam also showed significantly greater activity than sulbactam against the two groups of Beta-Lactamases. There were no significant differences between the overall activities of tazobactam and clavulanic acid against the extended-spectrum TEM and SHV enzymes and conventional-spectrum enzymes, although differences in their inhibition profiles were observed.
Aranapakam Mudumbai Venkatesan - One of the best experts on this subject based on the ideXlab platform.
-
5 5 6 fused tricycles bearing imidazole and pyrazole 6 methylidene penems as broad spectrum Inhibitors of β lactamases
Bioorganic & Medicinal Chemistry, 2008Co-Authors: Aranapakam Mudumbai Venkatesan, Takao Abe, Mihira Ado, Atul Agarwal, Hideki Ushirogochi, Takasaki Tsuyoshi, Osvaldo Dos Santos, Gerry Francisco, Yang I Lin, Peter PetersenAbstract:Beta-Lactamases are serine- and metal-dependent hydrolases, produced by the bacteria as defense against beta-lactam antibiotics. Commercially available Inhibitors such as clavulanic acid, sulbactam, and tazobactam, which are currently used in the hospital settings, have reduced activity against newly emerging Beta-Lactamases. Bacterial production of diverse Beta-Lactamases including class-A, class-C, and ESBLs has motivated several research groups to search for Inhibitors with a broader spectrum of activity. Previously, several novel 6-methylidene penems bearing, [5,5] [5,6] and [5,5,5] heterocycles have been synthesized in our laboratory and were shown to be potent and broad-spectrum Beta-Lactamase Inhibitors. As a continuation of our previous work and in order to extend the structure-activity relationships, in this paper, we describe herein the synthesis and in vitro, in vivo activities of several novel 5,5,6-fused tricyclic heterocycles attached to the 6-methylidene penem core. The compounds presented in the current paper are potent and broad-spectrum Inhibitors of the TEM-1 and AmpC Beta-Lactamases. In combination with piperacillin, their in vitro activities showed enhanced susceptibility to class A- and C-resistant strains studied in various bacteria. Some of the newly synthesized compounds such as 12a-c were shown to have in vivo activity in the acute lethal infection model against TEM-1 producing organisms. The 5,5,6-fused heterocyclic ring cores such as 21, 25, and 35 reported here are hitherto unknown in the literature.
-
Structure-Activity Relationship of 6-Methylidene Penems Bearing 6,5 Bicyclic Heterocycles as Broad-Spectrum β-Lactamase Inhibitors: Evidence for 1,4-Thiazepine Intermediates with C7 R Stereochemistry by Computational Methods
Journal of medicinal chemistry, 2006Co-Authors: Aranapakam Mudumbai Venkatesan, Takao Abe, Mihira Ado, Atul Agarwal, Hideki Ushirogochi, Itsuka Yamamura, Takasaki Tsuyoshi, Osvaldo Dos Santos, Fuk-wah SumAbstract:The design and synthesis of a series of 6-methylidene penems containing [6,5]-fused bicycles (thiophene, imidazole, or pyrazle-fused system) as novel class A, B, and C Beta-Lactamase Inhibitors is described. These penems proved to be potent Inhibitors of the TEM-1 (class A) and AmpC (class C) Beta-Lactamases and less so against the class B metallo-Beta-Lactamase CcrA. Their in vitro and in vivo activities in combination with piperacillin are discussed. On the basis of the crystallographic structures of a serine-bound reaction intermediate of 2 with SHV-1 (class A) and GC1 (class C) enzymes, compounds 14a-l were designed and synthesized. Penems are proposed to form a seven-membered 1,4 thiazepine ring in both class A and C Beta-Lactamases. The interaction energy calculation for the enzyme-bound intermediates favor the formation of the C7 R enantiomer over the S enantiomer of the 1,4-thiazepine in both Beta-Lactamases, which is consistent with those obtained from the crystal structure of 2 with SHV-1 and GC1.
Jean-marie Frère - One of the best experts on this subject based on the ideXlab platform.
-
dynamic combinatorial mass spectrometry leads to metallo beta lactamase Inhibitors
Journal of Medicinal Chemistry, 2008Co-Authors: Benoit M R Lienard, Jean-marie Frère, Moreno Galleni, Rebekka Huting, Patricia Lassaux, Christopher J SchofieldAbstract:The use of protein ESI mass spectrometry under non-denaturing conditions to analyze a dynamic combinatorial library of thiols/disulfides with the BcII metallo-β-lactamase enabled the rapid identification of an inhibitor with a Ki of <1 µM. The study exemplifies the utility of protein-MS for screening dynamic mixtures of potential enzyme–Inhibitors.
-
beta lactamase Inhibitors derived from single domain antibody fragments elicited in the camelidae
Antimicrobial Agents and Chemotherapy, 2001Co-Authors: Katja Conrath, Jean-marie Frère, Lode Wyns, Marc Lauwereys, Moreno Galleni, André Matagne, Jorg Kinne, Serge MuyldermansAbstract:Small, soluble single-domain fragments derived from the unique variable region of dromedary heavy-chain antibodies (VHHs) against enzymes are known to be potent Inhibitors. The immunization of dromedaries with the TEM-1 and BcII β-lactamases has lead to the isolation of such single-domain antibody fragments specifically recognizing and inhibiting those β-lactamases. Two VHHs were isolated that inhibit TEM-1 and one BcII inhibiting VHH was identified. All inhibitory VHHs were tight-binding Inhibitors. The 50% inhibitory concentrations were determined for all Inhibitors and they were all in the same range as the enzyme concentration used in the assay. Addition of the VHHs to the TEM-1 β-lactamase, expressed on the surface of bacteria, leads to a higher ampicillin sensitivity of the bacteria. This innovative strategy could generate multiple potent Inhibitors for all types of β-lactamases.
-
Catalytic properties of class A Beta-Lactamases: efficiency and diversity.
The Biochemical journal, 1998Co-Authors: André Matagne, Josette Lamotte-brasseur, Jean-marie FrèreAbstract:Beta-Lactamases are the main cause of bacterial resistance to penicillins, cephalosporins and related beta-lactam compounds. These enzymes inactivate the antibiotics by hydrolysing the amide bond of the beta-lactam ring. Class A Beta-Lactamases are the most widespread enzymes and are responsible for numerous failures in the treatment of infectious diseases. The introduction of new beta-lactam compounds, which are meant to be 'Beta-Lactamase-stable' or Beta-Lactamase Inhibitors, is thus continuously challenged either by point mutations in the ubiquitous TEM and SHV plasmid-borne Beta-Lactamase genes or by the acquisition of new genes coding for Beta-Lactamases with different catalytic properties. On the basis of the X-ray crystallography structures of several class A Beta-Lactamases, including that of the clinically relevant TEM-1 enzyme, it has become possible to analyse how particular structural changes in the enzyme structures might modify their catalytic properties. However, despite the many available kinetic, structural and mutagenesis data, the factors explaining the diversity of the specificity profiles of class A Beta-Lactamases and their amazing catalytic efficiency have not been thoroughly elucidated. The detailed understanding of these phenomena constitutes the cornerstone for the design of future generations of antibiotics.
David J Payne - One of the best experts on this subject based on the ideXlab platform.
-
comparative activities of clavulanic acid sulbactam and tazobactam against clinically important beta lactamases
Antimicrobial Agents and Chemotherapy, 1994Co-Authors: David J Payne, R Cramp, D J Winstanley, D KnowlesAbstract:Clavulanic acid, sulbactam, and tazobactam are Inhibitors of a variety of plasmid-mediated Beta-Lactamases. However, inhibition data for these three Inhibitors with a wide range of different plasmid-mediated Beta-Lactamases have not yet been compared under the same experimental conditions. A number of groups have inferred that clavulanic acid inhibits extended-spectrum TEM and SHV Beta-Lactamases, but inhibition data have rarely been published. In this study, the 50% inhibitory concentrations of these three Beta-Lactamase Inhibitors for 35 plasmid-mediated Beta-Lactamases have been determined. Of these 35 Beta-Lactamases, 20 were extended-spectrum TEM- or SHV-derived Beta-Lactamases. The other 15 enzymes were conventional-spectrum Beta-Lactamases such as TEM-1 and SHV-1. Clavulanic acid was a more potent inhibitor than sulbactam for 32 of the 35 plasmid-mediated Beta-Lactamases tested. In particular, clavulanic acid was 60 and 580 times more potent than sulbactam against TEM-1 and SHV-1, respectively, currently the two most clinically prevalent gram-negative plasmid-mediated Beta-Lactamases. Statistical analysis of the data of the 50% inhibitory concentrations showed that clavulanic acid was 20 times more active overall than sulbactam against the conventional-spectrum enzymes. In addition, clavulanic acid was 14 times more potent than sulbactam at inhibiting the extended-spectrum enzymes. Tazobactam also showed significantly greater activity than sulbactam against the two groups of Beta-Lactamases. There were no significant differences between the overall activities of tazobactam and clavulanic acid against the extended-spectrum TEM and SHV enzymes and conventional-spectrum enzymes, although differences in their inhibition profiles were observed.
-
comparative activities of clavulanic acid sulbactam and tazobactam against clinically important beta lactamases
Antimicrobial Agents and Chemotherapy, 1994Co-Authors: David J Payne, R Cramp, D J Winstanley, D KnowlesAbstract:Clavulanic acid, sulbactam, and tazobactam are Inhibitors of a variety of plasmid-mediated Beta-Lactamases. However, inhibition data for these three Inhibitors with a wide range of different plasmid-mediated Beta-Lactamases have not yet been compared under the same experimental conditions. A number of groups have inferred that clavulanic acid inhibits extended-spectrum TEM and SHV Beta-Lactamases, but inhibition data have rarely been published. In this study, the 50% inhibitory concentrations of these three Beta-Lactamase Inhibitors for 35 plasmid-mediated Beta-Lactamases have been determined. Of these 35 Beta-Lactamases, 20 were extended-spectrum TEM- or SHV-derived Beta-Lactamases. The other 15 enzymes were conventional-spectrum Beta-Lactamases such as TEM-1 and SHV-1. Clavulanic acid was a more potent inhibitor than sulbactam for 32 of the 35 plasmid-mediated Beta-Lactamases tested. In particular, clavulanic acid was 60 and 580 times more potent than sulbactam against TEM-1 and SHV-1, respectively, currently the two most clinically prevalent gram-negative plasmid-mediated Beta-Lactamases. Statistical analysis of the data of the 50% inhibitory concentrations showed that clavulanic acid was 20 times more active overall than sulbactam against the conventional-spectrum enzymes. In addition, clavulanic acid was 14 times more potent than sulbactam at inhibiting the extended-spectrum enzymes. Tazobactam also showed significantly greater activity than sulbactam against the two groups of Beta-Lactamases. There were no significant differences between the overall activities of tazobactam and clavulanic acid against the extended-spectrum TEM and SHV enzymes and conventional-spectrum enzymes, although differences in their inhibition profiles were observed.