Dataset Information

Novel Beta-Lactamase Inhibitors: Unlocking Their Potential in Therapy.

ABSTRACT: Carbapenem-resistant Enterobacteriaceae are amongst the most feared pathogens due to severely limited treatment options. In response to this threat, three novel ?-lactamase inhibitors have been developed in an attempt to reinvigorate and sustain our current antimicrobial therapies. Avibactam, vaborbactam, and relebactam are inhibitor agents with high affinity to Ambler class A and C ?-lactamases and favorable outcomes in current clinical trials. However, although they do possess key similarities, these agents have unique differences which may have important clinical implications. The microbiologic spectrum, pharmacokinetics, and key clinical trials for each of these novel agents are reviewed. A proposed role in therapy and potential novel combinations are examined.

SUBMITTER: Wong D

PROVIDER: S-EPMC5473160 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Novel Beta-Lactamase Inhibitors: Unlocking Their Potential in Therapy.

Wong Darren D van Duin David D

Drugs 20170401 6

Carbapenem-resistant Enterobacteriaceae are amongst the most feared pathogens due to severely limited treatment options. In response to this threat, three novel β-lactamase inhibitors have been developed in an attempt to reinvigorate and sustain our current antimicrobial therapies. Avibactam, vaborbactam, and relebactam are inhibitor agents with high affinity to Ambler class A and C β-lactamases and favorable outcomes in current clinical trials. However, although they do possess key similarities ...[more]

PMID: 28303449

Similar Datasets

Project description:?-lactam antibiotics are the most widely used antimicrobial agents since the discovery of benzylpenicillin in the 1920s. Unfortunately, these life-saving antibiotics are vulnerable to inactivation by continuously evolving ?-lactamase enzymes that are primary resistance determinants in multi-drug resistant pathogens. The current study exploits the strategy of combination therapeutics and aims at identifying novel ?-lactamase inhibitors that can inactivate the ?-lactamase enzyme of the pathogen while allowing the ?-lactam antibiotic to act against its penicillin-binding protein target. Inhibitor discovery applied the Site-Identification by Ligand Competitive Saturation (SILCS) technology to map the functional group requirements of the ?-lactamase CMY-10 and generate pharmacophore models of active site. SILCS-MC, Ligand-grid Free Energy (LGFE) analysis and Machine-learning based random-forest (RF) scoring methods were then used to screen and filter a library of 700,000 compounds. From the computational screens 74 compounds were subjected to experimental validation in which ?-lactamase activity assay, in vitro susceptibility testing, and Scanning Electron Microscope (SEM) analysis were conducted to explore their antibacterial potential. Eleven compounds were identified as enhancers while 7 compounds were recognized as inhibitors of CMY-10. Of these, compound 11 showed promising activity in ?-lactamase activity assay, in vitro susceptibility testing against ATCC strains (E. coli, E. cloacae, E. agglomerans, E. alvei) and MDR clinical isolates (E. cloacae, E. alvei and E. agglomerans), with synergistic assay indicating its potential as a ?-lactam enhancer and ?-lactamase inhibitor. Structural similarity search against the active compound 11 yielded 28 more compounds. The majority of these compounds also exhibited ?-lactamase inhibition potential and antibacterial activity. The non-?-lactam-based ?-lactamase inhibitors identified in the current study have the potential to be used in combination therapy with lactam-based antibiotics against MDR clinical isolates that have been found resistant against last-line antibiotics.

Dataset Information

Novel Beta-Lactamase Inhibitors: Unlocking Their Potential in Therapy.

Publications

Novel Beta-Lactamase Inhibitors: Unlocking Their Potential in Therapy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets