Special Issue "Beta-Lactamases: Sequence, Structure, Function, and Inhibition"

A special issue of Biomolecules (ISSN 2218-273X).

Deadline for manuscript submissions: 20 February 2020.

Special Issue Editor

Dr. Peter Oelschlaeger
E-Mail Website
Guest Editor
Western University of Health Sciences, Pomona, United States
Interests: Antibiotic resistance; enzyme biochemistry; evolution and function of beta-lactamases; metallo-beta-lactamase inhibitors; Gram-negative infections and diabetes

Special Issue Information

Dear Colleagues,

Beta-lactamases represent the most prevalent antibiotic resistance mechanism. Their existence has been known since before penicillin was introduced into the clinic. Their action continues to challenge antimicrobial chemotherapy by prompting the need for the continued discovery and development of new beta-lactam antibiotics and beta-lactamase inhibitors. Bacteria have effectively countered these drug development efforts through the evolution of their beta-lactamase genes, yielding enzymes with extended substrate spectra and resistance to existing beta-lactamase inhibitors. A recently emerging class of enzymes, the metallo-beta-lactamases, are notorious for having broad substrate spectra and there are currently no inhibitors against them available in the clinic. This Special Issue focuses on the biomolecular characteristics of beta-lactamases, including their sequence and evolution, structure and biophysical properties, their function, and ways to combat their action.

Dr. Peter Oelschlaeger
Guest Editor

Manuscript Submission Information

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Keywords

  • beta-lactamase
  • antibiotic resistance
  • mechanism
  • evolution
  • inhibition

Published Papers (3 papers)

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Research

Open AccessFeature PaperArticle
Mutation S115T in IMP-Type Metallo-β-Lactamases Compensates for Decreased Expression Levels Caused by Mutation S119G
Biomolecules 2019, 9(11), 724; https://doi.org/10.3390/biom9110724 (registering DOI) - 11 Nov 2019
Abstract
(1) Background: Metallo-β-lactamases (MBLs) have raised concerns due to their ability to inactivate carbapenems and newer generation cephalosporins and the absence of clinically available MBL inhibitors. Their genes are often transferred horizontally, and the number of MBL variants has grown exponentially, with many [...] Read more.
(1) Background: Metallo-β-lactamases (MBLs) have raised concerns due to their ability to inactivate carbapenems and newer generation cephalosporins and the absence of clinically available MBL inhibitors. Their genes are often transferred horizontally, and the number of MBL variants has grown exponentially, with many newer variants showing enhanced enzyme activity or stability. In this study, we investigated a closely related group of variants from the IMP family that all contain the combination of mutations S115T and S119G relative to IMP-1. (2) Methods: The effects of each individual mutation and their combination in the IMP-1 sequence background in comparison to IMP-1 were investigated. Their ability to confer resistance and their in-cell expression levels were determined. All enzymes were purified, and their secondary structure and thermal stability were determined with circular dichroism. Their Zn(II) content and kinetic constants with a panel of β-lactam antibiotics were determined. (3) Results: All four enzymes were viable and conferred resistance to all antibiotics tested except aztreonam. However, the single-mutant enzymes were slightly deficient, IMP-1S115T due to decreased enzyme activity and IMP-1-S119G due to decreased thermal stability and expression, while the double mutant did not show these defects. (4) Conclusions: These observations suggest that S119G was acquired due to its increased enzyme activity and S115T to suppress the thermal stability and expression defect introduced by S119G. Full article
(This article belongs to the Special Issue Beta-Lactamases: Sequence, Structure, Function, and Inhibition)
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Open AccessCommunication
Dithiocarbamate as a Valuable Scaffold for the Inhibition of Metallo-β-Lactmases
Biomolecules 2019, 9(11), 699; https://doi.org/10.3390/biom9110699 - 05 Nov 2019
Abstract
The ‘superbug’ infection caused by metallo-β-lactamases (MβLs) has grown into an emergent health threat. Given the clinical importance of MβLs, a novel scaffold, dithiocarbamate, was constructed. The obtained molecules, DC1, DC8 and DC10, inhibited MβLs NDM-1, VIM-2, IMP-1, ImiS and L1 from all [...] Read more.
The ‘superbug’ infection caused by metallo-β-lactamases (MβLs) has grown into an emergent health threat. Given the clinical importance of MβLs, a novel scaffold, dithiocarbamate, was constructed. The obtained molecules, DC1, DC8 and DC10, inhibited MβLs NDM-1, VIM-2, IMP-1, ImiS and L1 from all three subclasses, exhibiting an IC50 < 26 μM. DC1 was found to be the best inhibitor of ImiS (IC50 < 0.22 μM). DC1-2, DC4, DC8 and DC10 restored antimicrobial effects of cefazolin and imipenem against E. coli-BL21, producing NDM-1, ImiS or L1, and DC1 showed the best inhibition of E. coli cells, expressing the three MβLs, resulting in a 2-16-fold reduction in the minimum inhibitory concentrations (MICs) of both antibiotics. Kinetics and isothermal titration calorimetry (ITC) assays showed that DC1 exhibited a reversible, and partially mixed inhibition, of NDM-1, ImiS and L1, with Ki values of 0.29, 0.14 and 5.06 µM, respectively. Docking studies suggest that the hydroxyl and carbonyl groups of DC1 form coordinate bonds with the Zn (II) ions, in the active center of NDM-1, ImiS and L1, thereby inhibiting the activity of the enzymes. Cytotoxicity assays showed that DC1, DC3, DC7 and DC9 have low toxicity in L929 mouse fibroblastic cells, at a dose of up to 250 μM. These studies revealed that the dithiocarbamate is a valuable scaffold for the development of MβLs inhibitors. Full article
(This article belongs to the Special Issue Beta-Lactamases: Sequence, Structure, Function, and Inhibition)
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Open AccessArticle
Nutrition Related Stress Factors Reduce the Transfer of Extended-Spectrum Beta-Lactamase Resistance Genes between an Escherichia coli Donor and a Salmonella Typhimurium Recipient In Vitro
Biomolecules 2019, 9(8), 324; https://doi.org/10.3390/biom9080324 - 31 Jul 2019
Abstract
The transfer of extended spectrum β-lactamase (ESBL)-genes occurs frequently between different bacteria species. The aim of this study was to investigate the impact of nutrition related stress factors on this transfer. Thus, an Escherichia coli donor and a Salmonella Typhimurium recipient were co-incubated [...] Read more.
The transfer of extended spectrum β-lactamase (ESBL)-genes occurs frequently between different bacteria species. The aim of this study was to investigate the impact of nutrition related stress factors on this transfer. Thus, an Escherichia coli donor and a Salmonella Typhimurium recipient were co-incubated for 4 h in media containing different levels of the stress factors’ pH, osmolality, copper, zinc and acetic, propionic, lactic, and n-butyric acid, as well as subtherapeutic levels of cefotaxime, sulfamethoxazole/trimethoprim, and nitrofurantoin. Conjugation frequencies were calculated as transconjugants per donor, recipient, and total bacterial count. A correction factor for the stress impact on bacterial growth was used. Acetic, lactic, and n-butyric, acid, as well as pH, showed no significant impact. In contrast, increasing concentrations of propionate, zinc, copper, and nitrofurantoin, as well as increased osmolality reduced conjugation frequencies. Sulfamethoxazole/trimethoprim and cefotaxime showed increased transconjugants per donor, which decreased after correction for stress. This study showed, for the model mating pair, that conjugation frequencies decreased under different physiological stress conditions, and, thus, the hypothesis that stress factors may enhance conjugation should be viewed with caution. Furthermore, for studies on in vitro gene transfer, it is vital to consider the impact of studied stressors on bacterial growth. Full article
(This article belongs to the Special Issue Beta-Lactamases: Sequence, Structure, Function, and Inhibition)
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Figure 1

Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Type: Article
Tentative Title: Structural and Mechanistic Insights into β-Lactamase Inhibition
Author: Schofield C.J., Brem J., et al

Type: Review
Tentative Title: Mechanistic-based inhibitors of Metallo-beta-lactamases
Authors: Alejandro J. Vila, Antonela Palacios and Ma. Agustina Rossi

Type: Article
Tentative Title: Isothermal Titration Calorimetry (ITC) and β-Lactamase Inhibitors
Authors: Robert Bonomo, Chris Bethel and Magdalena Taracila
Affiliation: Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA

Type: Review
Tentative Title: The role of Ω–loop in the regulation of catalytic activity of class A beta-lactamases
Author: Alexey Egorov et al.
Affiliation: Moscow State University, Russia

Type: Article
Tentative Title: In silico identification and experimental validation of hits active against GES-5 beta-lactamase
Author: Raphael Klein, Donatella Tondi, Ruth Brenk
Affiliation: University of Bergen, Norway

Type: Article
Tentative Title: New class D enzyme
Author: Jean-Marie Frère et al.
Affiliation: Institut de Chimie B6a Sart-Tilman, Liège, Belgium

Type: Review
Tentative Title: Inhibition of beta-lactamses: a hope against the growing menace of multidruyge resistance
Author: Maria S. Ramirez, Robert A. Bonomo, Marcelo E. Tolmasky
Affiliation: California State University, Fullerton

Type: Article
Tentative Title: MBLinhibitors.com, a website resource offering information and expertise for the continued development of MBL inhibitors
Author: Michael W. Crowder, Zishuo Cheng, Caitlyn Thomas et al.
Affiliation: Department of Chemistry and Biochemistry, Miami University

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