JBIR-155, a Specific Class D β-Lactamase Inhibitor of Microbial Origin

2021 ◽  
Author(s):  
Takehiro Nishimura ◽  
Teppei Kawahara ◽  
Noritaka Kagaya ◽  
Yusuke Ogura ◽  
Hirosato Takikawa ◽  
...  
Keyword(s):  
Specific Class ◽  
Microbial Origin ◽  
Class D ◽  
Lactamase Inhibitor

scholarly journals Safety and Pharmacokinetic Characterization of Nacubactam, a Novel β-Lactamase Inhibitor, Alone and in Combination with Meropenem, in Healthy Volunteers

2020 ◽  
Vol 64 (5) ◽  
Author(s):  
Navita L. Mallalieu ◽  
Erica Winter ◽  
Scott Fettner ◽  
Katie Patel ◽  
Elke Zwanziger ◽  
...  
Keyword(s):  
Dose Range ◽  
Drug Dose ◽  
Test Results ◽  
Safety Test ◽  
Class D ◽  
Apparent Relationship ◽  
Dose Study ◽  
Relevant Dose ◽  
Lactamase Inhibitor

ABSTRACT Nacubactam is a novel β-lactamase inhibitor with dual mechanisms of action as an inhibitor of serine β-lactamases (classes A and C and some class D) and an inhibitor of penicillin binding protein 2 in Enterobacteriaceae. The safety, tolerability, and pharmacokinetics of intravenous nacubactam were evaluated in single- and multiple-ascending-dose, placebo-controlled studies. Healthy participants received single ascending doses of nacubactam of 50 to 8,000 mg, multiple ascending doses of nacubactam of 1,000 to 4,000 mg every 8 h (q8h) for up to 7 days, or nacubactam of 2,000 mg plus meropenem of 2,000 mg q8h for 6 days after a 3-day lead-in period. Nacubactam was generally well tolerated, with the most frequently reported adverse events (AEs) being mild to moderate complications associated with intravenous access and headache. There was no apparent relationship between drug dose and the pattern, incidence, or severity of AEs. No clinically relevant dose-related trends were observed in laboratory safety test results. No serious AEs, dose-limiting AEs, or deaths were reported. After single or multiple doses, nacubactam pharmacokinetics appeared linear, and exposure increased in an approximately dose-proportional manner across the dose range investigated. Nacubactam was excreted largely unchanged into urine. Coadministration of nacubactam with meropenem did not significantly alter the pharmacokinetics of either drug. These findings support the continued clinical development of nacubactam and demonstrate the suitability of meropenem as a potential β-lactam partner for nacubactam. (The studies described in this paper have been registered at ClinicalTrials.gov under NCT02134834 [single ascending dose study] and NCT02972255 [multiple ascending dose study].)

scholarly journals Primary structure of OXA-3 and phylogeny of oxacillin-hydrolyzing class D beta-lactamases.

1995 ◽  
Vol 39 (4) ◽  
pp. 887-893 ◽  
Author(s):  
F Sanschagrin ◽  
F Couture ◽  
R C Levesque
Keyword(s):  
Amino Acids ◽  
Structure And Function ◽  
Amino Acid Sequences ◽  
Specific Class ◽  
Conserved Motifs ◽  
Beta Lactamases ◽  
Class A ◽  
Class D ◽  
And Function ◽  
Conserved Amino Acids

We determined the nucleotide sequence of the blaOXA-3(pMG25) gene from Pseudomonas aeruginosa. The bla structural gene encoded a protein of 275 amino acids representing one monomer of 31,879 Da for the OXA-3 enzyme. Comparisons between the OXA-3 nucleotide and amino acid sequences and those of class A, B, C, and D beta-lactamases were performed. An alignment of the eight known class D beta-lactamases including OXA-3 demonstrated the presence of conserved amino acids. In addition, conserved motifs composed of identical amino acids typical of penicillin-recognizing proteins and specific class D motifs were identified. These conserved motifs were considered for possible roles in the structure and function of oxacillinases. On the basis of the alignment and identity scores, a dendrogram was constructed. The phylogenetic data obtained revealed five groups of class D beta-lactamases with large evolutionary distances between each group.

scholarly journals New Carbapenemase Inhibitors: Clearing the Way for the β-Lactams

2020 ◽  
Vol 21 (23) ◽  
pp. 9308
Author(s):  
Juan C. Vázquez-Ucha ◽  
Jorge Arca-Suárez ◽  
Germán Bou ◽  
Alejandro Beceiro
Keyword(s):  
Clinical Trials ◽  
Antimicrobial Resistance ◽  
Carbapenem Resistance ◽  
New Combinations ◽  
Stage Of Development ◽  
Class D ◽  
New Generation ◽  
Global Health Problem ◽  
Current Stage ◽  
Lactamase Inhibitor

Carbapenem resistance is a major global health problem that seriously compromises the treatment of infections caused by nosocomial pathogens. Resistance to carbapenems mainly occurs via the production of carbapenemases, such as VIM, IMP, NDM, KPC and OXA, among others. Preclinical and clinical trials are currently underway to test a new generation of promising inhibitors, together with the recently approved avibactam, relebactam and vaborbactam. This review summarizes the main, most promising carbapenemase inhibitors synthesized to date, as well as their spectrum of activity and current stage of development. We particularly focus on β-lactam/β-lactamase inhibitor combinations that could potentially be used to treat infections caused by carbapenemase-producer pathogens of critical priority. The emergence of these new combinations represents a step forward in the fight against antimicrobial resistance, especially in regard to metallo-β-lactamases and carbapenem-hydrolysing class D β-lactamases, not currently inhibited by any clinically approved inhibitor.

scholarly journals Avibactam and Inhibitor-Resistant SHV β-Lactamases

2015 ◽  
Vol 59 (7) ◽  
pp. 3700-3709 ◽  
Author(s):  
Marisa L. Winkler ◽  
Krisztina M. Papp-Wallace ◽  
Magdalena A. Taracila ◽  
Robert A. Bonomo
Keyword(s):  
Alternative Pathway ◽  
Proton Acceptor ◽  
Hydroxyl Group ◽  
The Novel ◽  
Content Type ◽  
Class A ◽  
Important Amino Acid ◽  
Class D ◽  
Continued Use ◽  
Lactamase Inhibitor

ABSTRACTβ-Lactamase enzymes (EC 3.5.2.6) are a significant threat to the continued use of β-lactam antibiotics to treat infections. A novel non-β-lactam β-lactamase inhibitor with activity against many class A and C and some class D β-lactamase variants, avibactam, is now available in the clinic in partnership with ceftazidime. Here, we explored the activity of avibactam against a variety of characterized isogenic laboratory constructs of β-lactamase inhibitor-resistant variants of the class A enzyme SHV (M69I/L/V, S130G, K234R, R244S, and N276D). We discovered that the S130G variant of SHV-1 shows the most significant resistance to inhibition by avibactam, based on both microbiological and biochemical characterizations. Using a constant concentration of 4 mg/liter of avibactam as a β-lactamase inhibitor in combination with ampicillin, the MIC increased from 1 mg/liter forblaSHV-1to 256 mg/liter forblaSHV S130Gexpressed inEscherichia coliDH10B. At steady state, thek2/Kvalue of the S130G variant when inactivated by avibactam was 1.3 M−1s−1, versus 60,300 M−1s−1for the SHV-1 β-lactamase. Under timed inactivation conditions, we found that an approximately 1,700-fold-higher avibactam concentration was required to inhibit SHV S130G than the concentration that inhibited SHV-1. Molecular modeling suggested that the positioning of amino acids in the active site of SHV may result in an alternative pathway of inactivation when complexed with avibactam, compared to the structure of CTX-M-15–avibactam, and that S130 plays a role in the acylation of avibactam as a general acid/base. In addition, S130 may play a role in recyclization. As a result, we advance that the lack of a hydroxyl group at position 130 in the S130G variant of SHV-1 substantially slows carbamylation of the β-lactamase by avibactam by (i) removing an important proton acceptor and donator in catalysis and (ii) decreasing the number of H bonds. In addition, recyclization is most likely also slow due to the lack of a general base to initiate the process. Considering other inhibitor-resistant mechanisms among class A β-lactamases, S130 may be the most important amino acid for the inhibition of class A β-lactamases, perhaps even for the novel diazabicyclooctane class of β-lactamase inhibitors.

scholarly journals Activity of the β-Lactamase Inhibitor LN-1-255 against Carbapenem-Hydrolyzing Class D β-Lactamases from Acinetobacter baumannii

2017 ◽  
Vol 61 (11) ◽  
Author(s):  
Juan Carlos Vázquez-Ucha ◽  
María Maneiro ◽  
Marta Martínez-Guitián ◽  
John Buynak ◽  
Christopher R. Bethel ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Multidrug Resistant ◽  
Kinetics Parameters ◽  
Clinical Issue ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Class D ◽  
Continued Use ◽  
Global Threat ◽  
Lactamase Inhibitor

ABSTRACT The number of infections caused by Gram-negative pathogens carrying carbapenemases is increasing, and the group of carbapenem-hydrolyzing class D β-lactamases (CHDLs) is especially problematic. Several clinically important CHDLs have been identified in Acinetobacter baumannii, including OXA-23, OXA-24/40, OXA-58, OXA-143, OXA-235, and the chromosomally encoded OXA-51. The selection and dissemination of carbapenem-resistant A. baumannii strains constitutes a serious global threat. Carbapenems have been successfully utilized as last-resort antibiotics for the treatment of multidrug-resistant A. baumannii infections. However, the spread of OXA carbapenemases is compromising the continued use of these antimicrobials. In response to this clinical issue, it is necessary and urgent to design and develop new specific inhibitors with efficacy against these enzymes. The aim of this work was to characterize the inhibitory activity of LN-1-255 (a 6-alkylidene-2-substituted penicillin sulfone) and compare it to that of two established inhibitors (avibactam and tazobactam) against the most relevant enzymes of each group of class D carbapenemases in A. baumannii. The β-lactamase inhibitor LN-1-255 demonstrated excellent microbiological synergy and inhibition kinetics parameters against all tested CHDLs and a significantly higher activity than tazobactam and avibactam. A combination of carbapenems and LN-1-255 was effective against A. baumannii class D carbapenemases. Docking assays confirmed the affinity of LN-1-255 for the active site of these enzymes. LN-1-255 represents a potential new β-lactamase inhibitor that may have a significant role in eradicating infections caused by A. baumannii isolates carrying CHDLs.

scholarly journals In VitroandIn VivoProperties of BAL30376, a β-Lactam and Dual β-Lactamase Inhibitor Combination with Enhanced Activity against Gram-Negative Bacilli That Express Multiple β-Lactamases

2011 ◽  
Vol 55 (4) ◽  
pp. 1510-1519 ◽  
Author(s):  
Malcolm G. P. Page ◽  
Clothilde Dantier ◽  
Eric Desarbre ◽  
Bérangère Gaucher ◽  
Klaus Gebhardt ◽  
...  
Keyword(s):  
Clavulanic Acid ◽  
Stenotrophomonas Maltophilia ◽  
Multidrug Resistant ◽  
Triple Combination ◽  
Class A ◽  
Link Type ◽  
Class D ◽  
Class C ◽  
Inhibitor Combination ◽  
Lactamase Inhibitor

ABSTRACTBAL30376 is a triple combination comprising a siderophore monobactam,BAL19764; a novel bridged monobactam,BAL29880, which specifically inhibits class C β-lactamases; and clavulanic acid, which inhibits many class A and some class D β-lactamases. The MIC90was ≤4 μg/ml (expressed as the concentration ofBAL19764) for most species of theEnterobacteriaceaefamily, including strains that produced metallo-β-lactamases and were resistant to all of the other β-lactams tested. The MIC90forStenotrophomonas maltophiliawas 2 μg/ml, for multidrug-resistant (MDR)Pseudomonas aeruginosait was 8 μg/ml, and for MDRAcinetobacterandBurkholderiaspp. it was 16 μg/ml. The presence of the class C β-lactamase inhibitorBAL29880contributed significantly to the activity ofBAL30376against strains ofCitrobacter freundii,Enterobacterspecies,Serratia marcescens, andP. aeruginosa. The presence of clavulanic acid contributed significantly to the activity against many strains ofEscherichia coliandKlebsiella pneumoniaethat produced class A extended-spectrum β-lactamases. The activity ofBAL30376against strains with metallo-β-lactamases was largely attributable to the intrinsic stability of the monobactamBAL19764toward these enzymes. Considering its three components,BAL30376was unexpectedly refractory toward the development of stable resistance.

scholarly journals New β-Lactam–β-Lactamase Inhibitor Combinations

2020 ◽  
Vol 34 (1) ◽  
Author(s):  
Dafna Yahav ◽  
Christian G. Giske ◽  
Alise Grāmatniece ◽  
Henrietta Abodakpi ◽  
Vincent H. Tam ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Treatment Option ◽  
Clinical Data ◽  
Multidrug Resistant ◽  
Drug Resistant ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Class D ◽  
Lactamase Inhibitor

SUMMARY The limited armamentarium against drug-resistant Gram-negative bacilli has led to the development of several novel β-lactam–β-lactamase inhibitor combinations (BLBLIs). In this review, we summarize their spectrum of in vitro activities, mechanisms of resistance, and pharmacokinetic-pharmacodynamic (PK-PD) characteristics. A summary of available clinical data is provided per drug. Four approved BLBLIs are discussed in detail. All are options for treating multidrug-resistant (MDR) Enterobacterales and Pseudomonas aeruginosa. Ceftazidime-avibactam is a potential drug for treating Enterobacterales producing extended-spectrum β-lactamase (ESBL), Klebsiella pneumoniae carbapenemase (KPC), AmpC, and some class D β-lactamases (OXA-48) in addition to carbapenem-resistant Pseudomonas aeruginosa. Ceftolozane-tazobactam is a treatment option mainly for carbapenem-resistant P. aeruginosa (non-carbapenemase producing), with some activity against ESBL-producing Enterobacterales. Meropenem-vaborbactam has emerged as treatment option for Enterobacterales producing ESBL, KPC, or AmpC, with similar activity as meropenem against P. aeruginosa. Imipenem-relebactam has documented activity against Enterobacterales producing ESBL, KPC, and AmpC, with the combination having some additional activity against P. aeruginosa relative to imipenem. None of these drugs present in vitro activity against Enterobacterales or P. aeruginosa producing metallo-β-lactamase (MBL) or against carbapenemase-producing Acinetobacter baumannii. Clinical data regarding the use of these drugs to treat MDR bacteria are limited and rely mostly on nonrandomized studies. An overview on eight BLBLIs in development is also provided. These drugs provide various levels of in vitro coverage of carbapenem-resistant Enterobacterales, with several drugs presenting in vitro activity against MBLs (cefepime-zidebactam, aztreonam-avibactam, meropenem-nacubactam, and cefepime-taniborbactam). Among these drugs, some also present in vitro activity against carbapenem-resistant P. aeruginosa (cefepime-zidebactam and cefepime-taniborbactam) and A. baumannii (cefepime-zidebactam and sulbactam-durlobactam).

scholarly journals In VivoEfficacy of Humanized Exposures of Ceftazidime-Avibactam in Comparison with Ceftazidime against Contemporary Enterobacteriaceae Isolates

2014 ◽  
Vol 58 (11) ◽  
pp. 6913-6919 ◽  
Author(s):  
Shawn H. MacVane ◽  
Jared L. Crandon ◽  
Wright W. Nichols ◽  
David P. Nicolau
Keyword(s):  
Gram Negative ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Class D ◽  
Variable Activity ◽  
Resistant Strains ◽  
The Impact ◽  
Inhibitor Combination ◽  
Lactamase Inhibitor

ABSTRACTCeftazidime-avibactam is a β-lactam β-lactamase inhibitor combination under investigation for the treatment of serious Gram-negative infections. When combined with avibactam, a novel non-β-lactam β-lactamase inhibitor, ceftazidime has activity against isolates that produce Ambler class A, class C, and some class D β-lactamases. However, little is known of thein vivoefficacy of the combination against these targeted ceftazidime- and carbapenem-resistantEnterobacteriaceae. Using humanized exposures in the murine thigh model, we evaluated the efficacy of ceftazidime-avibactam againstEnterobacteriaceaeexhibiting MICs of ≥8 μg/ml to aid in the assignment of interpretive susceptibility criteria. Eighteen clinicalEnterobacteriaceaeisolates, including nine carbapenem-resistant strains, were evaluated against ceftazidime-avibactam (2,000 mg/500 mg) as a 2-h infusion every 8 h. To highlight the impact of avibactam, 13 select isolates were tested in the neutropenic model against a humanized regimen of 2,000 mg ceftazidime every 8 h (2-h infusion). Additionally, nine isolates were evaluated in immunocompetent animals. The efficacy was evaluated as the change in log10CFU compared with that of 0-h controls after 24 h. The vast majority (17/18, 94%) of the isolates were resistant to ceftazidime alone. The ceftazidime monotherapy failed to have activity against 10 of 13 isolates, while ceftazidime-avibactam produced reductions in bacterial density against 16 of 18 isolates. Ceftazidime-avibactam (2,000 mg/500 mg) every 8 h (2-h infusion) displayed dependable activity against theEnterobacteriaceaeisolates, exhibiting MICs of ≤16 μg/ml (free drug concentration above the MIC [fT>MIC] of ≥62%) and variable activity was noted at an MIC of 32 μg/ml (fT>MICof 34%). The presence of a functioning immune system enhanced the efficacy for both regimens against all tested isolates. These data support further examination of the use of ceftazidime-avibactam as an effective therapy against infections due to Gram-negative infections, including carbapenem-resistantEnterobacteriaceae.

scholarly journals In Vitro and In Vivo Activities of AM-112, a Novel Oxapenem

2003 ◽  
Vol 47 (5) ◽  
pp. 1652-1657 ◽  
Author(s):  
Conor E. Jamieson ◽  
Peter A. Lambert ◽  
Iain N. Simpson
Keyword(s):  
Clavulanic Acid ◽  
Enterobacter Cloacae ◽  
Penicillin Binding Proteins ◽  
Class A ◽  
Sepsis Model ◽  
Class D ◽  
Class C ◽  
Lactamase Inhibitor

ABSTRACT AM-112 [(1′R,5R,6R)-3-(4-amino-1,1-dimethyl-butyl)-6-(1′-hydroxyethyl)oxapenem-3-carboxylate] is a novel oxapenem compound which possesses potent β-lactamase-inhibitory properties. Fifty-percent inhibitory concentrations (IC50s) of AM-112 for class A enzymes were between 0.16 and 2.24 μM for three enzymes, compared to IC50s of 0.008 to 0.12 μM for clavulanic acid. Against class C and class D enzymes, however, the activity of AM-112 was between 1,000- and 100,000-fold greater than that of clavulanic acid. AM-112 had affinity for the penicillin-binding proteins (PBPs) of Escherichia coli DC0, with PBP2 being inhibited by the lowest concentration of AM-112 tested, 0.1 μg/ml. Ceftazidime was combined with AM-112 at 1:1 and 2:1 ratios in MIC determination studies against a panel of β-lactamase-producing organisms. These studies demonstrated that AM-112 was effective at protecting ceftazidime against extended-spectrum β-lactamase-producing strains and derepressed class C enzyme producers, reducing ceftazidime MICs by 16- and 2,048-fold. Similar results were obtained when AM-112 was combined with ceftriaxone, cefoperazone, or cefepime in a 1:2 ratio. Protection of ceftazidime with AM-112 was maintained against Enterobacter cloacae P99 and Klebsiella pneumoniae SHV-5 in a murine intraperitoneal sepsis model. The 50% effective dose of ceftazidime against E. cloacae P99 and K. pneumoniae SHV-5 was reduced from >100 and 160 mg/kg of body weight to 2 and 33.6 mg/kg, respectively, when it was combined with AM-112 at a 1:1 ratio. AM-112 demonstrates potential as a new β-lactamase inhibitor.

scholarly journals High-Stringency Evaluation of the Automated BD Phoenix CPO Detect and Rapidec Carba NP Tests for Detection and Classification of Carbapenemases

2017 ◽  
Vol 55 (12) ◽  
pp. 3437-3443 ◽  
Author(s):  
Gina Thomson ◽  
David Turner ◽  
William Brasso ◽  
Susan Kircher ◽  
Thierry Guillet ◽  
...  
Keyword(s):  
Empirical Therapy ◽  
High Sensitivity ◽  
Content Type ◽  
Class A ◽  
Class D ◽  
Class B ◽  
Susceptibility Tests ◽  
Positive Results ◽  
Lactamase Inhibitor

ABSTRACTThere is an urgent need for rapid, accurate detection and classification of carbapenemases. The current study evaluated the automated BD Phoenix CPO Detect and the manual bioMérieux Rapidec Carba NP tests for meeting these needs. Both tests were challenged with 294 isolates ofEnterobacteriaceaespp.,Pseudomonas aeruginosa, andAcinetobacter baumanniichosen to provide extreme diagnostic difficulty. Carbapenemases such as KPC, NMC-A, IMI, SME, NDM, SPM, IMP, VIM, and OXA-23, 40, 48, 58, 72, 181, and 232 were produced by 243 isolates and 51 carbapenemase-negative isolates included porin mutants and producers of extended-spectrum β-lactamases (ESBLs), AmpCs, K1, and broad-spectrum β-lactamases. Both tests exhibited high sensitivity of carbapenemase detection (>97%). Due to the highly challenging carbapenemase-negative isolates, specificities were lower than typical for evaluations involving mostly routine clinical isolates. BD Phoenix CPO Detect was 68.6% specific and Rapidec Carba NP was 60.8% to 78.4% specific, depending on how borderline results were interpreted. Only BD Phoenix CPO Detect classified carbapenemases. It correctly classified 85.0% of class A, 72.4% of class B, and 88.6% of class D carbapenemases. Importantly with respect to empirical therapy with new β-lactamase inhibitor combinations such as ceftazidime/avibactam, no class B carbapenemases were misclassified as class A carbapenemases. Both tests offer advantages. Used alone, without initial susceptibility tests, Rapidec Carba NP can provide positive results for some isolates after only 10 to 30 min incubation. BD Phoenix CPO Detect provides novel advantages such as automated carbapenemase detection, inclusion in susceptibility panels to eliminate delays and subjectivity in initiating carbapenemase tests, and classification of most carbapenemases.

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