Submit to Biomolecules Review for Biomolecules Propose a Special Issue

Journal Browser

► Journal Browser

Beta-Lactamases: Sequence, Structure, Function, and Inhibition

Special Issue Editors
Special Issue Information
Keywords
Published Papers

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

Deadline for manuscript submissions: closed (20 April 2020) | Viewed by 64275

Share This Special Issue

Special Issue Editor

Dr. Peter Oelschlaeger

E-Mail Website
Guest Editor

Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA, USA
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

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

beta-lactamase
antibiotic resistance
mechanism
evolution
inhibition

Published Papers (14 papers)

Download All Papers

Editorial

Jump to: Research, Review

4 pages, 200 KiB

Open AccessEditorial

β-Lactamases: Sequence, Structure, Function, and Inhibition

by Peter Oelschlaeger

Biomolecules 2021, 11(7), 986; https://doi.org/10.3390/biom11070986 - 5 Jul 2021

Cited by 3 | Viewed by 2728

Abstract

β-Lactams were the first class of antibiotics to be discovered and the second to be introduced into the clinic in the 1940s [...] Full article

(This article belongs to the Special Issue Beta-Lactamases: Sequence, Structure, Function, and Inhibition)

Research

Jump to: Editorial, Review

18 pages, 7375 KiB

Open AccessArticle

4-(N-Alkyl- and -Acyl-amino)-1,2,4-triazole-3-thione Analogs as Metallo-β-Lactamase Inhibitors: Impact of 4-Linker on Potency and Spectrum of Inhibition

by Laurent Gavara, Federica Verdirosa, Alice Legru, Paola Sandra Mercuri, Lionel Nauton, Laurent Sevaille, Georges Feller, Dorothée Berthomieu, Filomena Sannio, Francesca Marcoccia, Silvia Tanfoni, Filomena De Luca, Nohad Gresh, Moreno Galleni, Jean-Denis Docquier and Jean-François Hernandez

Biomolecules 2020, 10(8), 1094; https://doi.org/10.3390/biom10081094 - 23 Jul 2020

Cited by 17 | Viewed by 2645

Abstract

To fight the increasingly worrying bacterial resistance to antibiotics, the discovery and development of new therapeutics is urgently needed. Here, we report on a new series of 1,2,4-triazole-3-thione compounds as inhibitors of metallo-β-lactamases (MBLs), which represent major resistance determinants to β-lactams, and especially carbapenems, in Gram-negative bacteria. These molecules are stable analogs of 4-amino-1,2,4-triazole-derived Schiff bases, where the hydrazone-like bond has been reduced (hydrazine series) or the 4-amino group has been acylated (hydrazide series); the synthesis and physicochemical properties thereof are described. The inhibitory potency was determined on the most clinically relevant acquired MBLs (IMP-, VIM-, and NDM-types subclass B1 MBLs). When compared with the previously reported hydrazone series, hydrazine but not hydrazide analogs showed similarly potent inhibitory activity on VIM-type enzymes, especially VIM-2 and VIM-4, with K_i values in the micromolar to submicromolar range. One of these showed broad-spectrum inhibition as it also significantly inhibited VIM-1 and NDM-1. Restoration of β-lactam activity in microbiological assays was observed for one selected compound. Finally, the binding to the VIM-2 active site was evaluated by isothermal titration calorimetry and a modeling study explored the effect of the linker structure on the mode of binding with this MBL. Full article

(This article belongs to the Special Issue Beta-Lactamases: Sequence, Structure, Function, and Inhibition)

► Show Figures

Figure 1

15 pages, 3674 KiB

Open AccessArticle

Bicyclic Boronates as Potent Inhibitors of AmpC, the Class C β-Lactamase from Escherichia coli

by Pauline A. Lang, Anete Parkova, Thomas M. Leissing, Karina Calvopiña, Ricky Cain, Alen Krajnc, Tharindi D. Panduwawala, Jules Philippe, Colin W. G. Fishwick, Peteris Trapencieris, Malcolm G. P. Page, Christopher J. Schofield and Jürgen Brem

Biomolecules 2020, 10(6), 899; https://doi.org/10.3390/biom10060899 - 12 Jun 2020

Cited by 20 | Viewed by 4759

Abstract

Resistance to β-lactam antibacterials, importantly via production of β-lactamases, threatens their widespread use. Bicyclic boronates show promise as clinically useful, dual-action inhibitors of both serine- (SBL) and metallo- (MBL) β-lactamases. In combination with cefepime, the bicyclic boronate taniborbactam is in phase 3 clinical trials for treatment of complicated urinary tract infections. We report kinetic and crystallographic studies on the inhibition of AmpC, the class C β-lactamase from Escherichia coli, by bicyclic boronates, including taniborbactam, with different C-3 side chains. The combined studies reveal that an acylamino side chain is not essential for potent AmpC inhibition by active site binding bicyclic boronates. The tricyclic form of taniborbactam was observed bound to the surface of crystalline AmpC, but not at the active site, where the bicyclic form was observed. Structural comparisons reveal insights into why active site binding of a tricyclic form has been observed with the NDM-1 MBL, but not with other studied β-lactamases. Together with reported studies on the structural basis of inhibition of class A, B and D β-lactamases, our data support the proposal that bicyclic boronates are broad-spectrum β-lactamase inhibitors that work by mimicking a high energy ‘tetrahedral’ intermediate. These results suggest further SAR guided development could improve the breadth of clinically useful β-lactamase inhibition. Full article

(This article belongs to the Special Issue Beta-Lactamases: Sequence, Structure, Function, and Inhibition)

► Show Figures

Graphical abstract

14 pages, 3043 KiB

Open AccessFeature PaperArticle

Structures of FOX-4 Cephamycinase in Complex with Transition-State Analog Inhibitors

by Scott T. Lefurgy, Emilia Caselli, Magdalena A. Taracila, Vladimir N. Malashkevich, Beena Biju, Krisztina M. Papp-Wallace, Jeffrey B. Bonanno, Fabio Prati, Steven C. Almo and Robert A. Bonomo

Biomolecules 2020, 10(5), 671; https://doi.org/10.3390/biom10050671 - 27 Apr 2020

Cited by 4 | Viewed by 2974

Abstract

Boronic acid transition-state analog inhibitors (BATSIs) are partners with β-lactam antibiotics for the treatment of complex bacterial infections. Herein, microbiological, biochemical, and structural findings on four BATSIs with the FOX-4 cephamycinase, a class C β-lactamase that rapidly hydrolyzes cefoxitin, are revealed. FOX-4 is an extended-spectrum class C cephalosporinase that demonstrates conformational flexibility when complexed with certain ligands. Like other β-lactamases of this class, studies on FOX-4 reveal important insights into structure–activity relationships. We show that SM23, a BATSI, shows both remarkable flexibility and affinity, binding similarly to other β-lactamases, yet retaining an IC₅₀ value < 0.1 μM. Our analyses open up new opportunities for the design of novel transition-state analogs of class C enzymes. Full article

(This article belongs to the Special Issue Beta-Lactamases: Sequence, Structure, Function, and Inhibition)

► Show Figures

Figure 1

14 pages, 1525 KiB

Open AccessFeature PaperArticle

Interactions between Avibactam and Ceftazidime-Hydrolyzing Class D β-Lactamases

by Jean-Marie Frère, Pierre Bogaerts, Te-Din Huang, Patrick Stefanic, Joël Moray, Fabrice Bouillenne and Alain Brans

Biomolecules 2020, 10(3), 483; https://doi.org/10.3390/biom10030483 - 23 Mar 2020

Cited by 7 | Viewed by 2487

Abstract

Class D β-lactamases exhibit very heterogeneous hydrolysis activity spectra against the various types of clinically useful β-lactams. Similarly, and according to the available data, their sensitivities to inactivation by avibactam can vary by a factor of more than 100. In this paper, we performed a detailed kinetic study of the interactions between two ceftazidime-hydrolyzing OXA enzymes and showed that they were significantly more susceptible to avibactam than several other class D enzymes that do not hydrolyze ceftazidime. From a clinical point of view, this result is rather interesting if one considers that avibactam is often administered in combination with ceftazidime. Full article

(This article belongs to the Special Issue Beta-Lactamases: Sequence, Structure, Function, and Inhibition)

► Show Figures

Graphical abstract

9 pages, 3292 KiB

Open AccessFeature PaperCommunication

MBLinhibitors.com, a Website Resource Offering Information and Expertise for the Continued Development of Metallo-β-Lactamase Inhibitors

by Zishuo Cheng, Caitlyn A. Thomas, Adam R. Joyner, Robert L. Kimble, Aidan M. Sturgill, Nhu-Y Tran, Maya R. Vulcan, Spencer A. Klinsky, Diego J. Orea, Cody R. Platt, Fanpu Cao, Bo Li, Qilin Yang, Cole J. Yurkiewicz, Walter Fast and Michael W. Crowder

Biomolecules 2020, 10(3), 459; https://doi.org/10.3390/biom10030459 - 16 Mar 2020

Cited by 9 | Viewed by 4485

Abstract

In an effort to facilitate the discovery of new, improved inhibitors of the metallo-β-lactamases (MBLs), a new, interactive website called MBLinhibitors.com was developed. Despite considerable efforts from the science community, there are no clinical inhibitors of the MBLs, which are now produced by human pathogens. The website, MBLinhibitors.com, contains a searchable database of known MBL inhibitors, and inhibitors can be searched by chemical name, chemical formula, chemical structure, Simplified Molecular-Input Line-Entry System (SMILES) format, and by the MBL on which studies were conducted. The site will also highlight a “MBL Inhibitor of the Month”, and researchers are invited to submit compounds for this feature. Importantly, MBLinhibitors.com was designed to encourage collaboration, and researchers are invited to submit their new compounds, using the “Submit” function on the site, as well as their expertise using the “Collaboration” function. The intention is for this site to be interactive, and the site will be improved in the future as researchers use the site and suggest improvements. It is hoped that MBLinhibitors.com will serve as the one-stop site for any important information on MBL inhibitors and will aid in the discovery of a clinically useful MBL inhibitor. Full article

(This article belongs to the Special Issue Beta-Lactamases: Sequence, Structure, Function, and Inhibition)

► Show Figures

Figure 1

10 pages, 4993 KiB

Open AccessArticle

Targeting the Class A Carbapenemase GES-5 via Virtual Screening

by Raphael Klein, Laura Cendron, Martina Montanari, Pierangelo Bellio, Giuseppe Celenza, Lorenzo Maso, Donatella Tondi and Ruth Brenk

Biomolecules 2020, 10(2), 304; https://doi.org/10.3390/biom10020304 - 14 Feb 2020

Cited by 1 | Viewed by 3888

Abstract

The worldwide spread of β-lactamases able to hydrolyze last resort carbapenems contributes to the antibiotic resistance problem and menaces the successful antimicrobial treatment of clinically relevant pathogens. Class A carbapenemases include members of the KPC and GES families. While drugs against KPC-type carbapenemases have recently been approved, for GES-type enzymes, no inhibitors have yet been introduced in therapy. Thus, GES carbapenemases represent important drug targets. Here, we present an in silico screening against the most prevalent GES carbapenemase, GES-5, using a lead-like compound library of commercially available compounds. The most promising candidates were selected for in vitro validation in biochemical assays against recombinant GES-5 leading to four derivatives active as high micromolar competitive inhibitors. For the best inhibitors, the ability to inhibit KPC-2 was also evaluated. The discovered inhibitors constitute promising starting points for hit to lead optimization. Full article

(This article belongs to the Special Issue Beta-Lactamases: Sequence, Structure, Function, and Inhibition)

► Show Figures

Figure 1

12 pages, 2150 KiB

Open AccessArticle

Kinetic, Thermodynamic, and Crystallographic Studies of 2-Triazolylthioacetamides as Verona Integron-Encoded Metallo-β-Lactamase 2 (VIM-2) Inhibitor

by Yang Xiang, Yue-Juan Zhang, Ying Ge, Yajun Zhou, Cheng Chen, Weixiao Yuan Wahlgren, Xiangshi Tan, Xi Chen and Ke-Wu Yang

Biomolecules 2020, 10(1), 72; https://doi.org/10.3390/biom10010072 - 1 Jan 2020

Cited by 7 | Viewed by 3117

Abstract

Inhibition of β-lactamases presents a promising strategy to restore the β-lactams antibacterial activity to resistant bacteria. In this work, we found that aromatic carboxyl substituted 2-triazolylthioacetamides 1a–j inhibited VIM-2, exhibiting an IC₅₀ value in the range of 20.6–58.6 μM. The structure-activity relationship study revealed that replacing the aliphatic carboxylic acid with aromatic carboxyl improved the inhibitory activity of 2-triazolylthioacetamides against VIM-2. 1a–j (16 mg/mL) restored the antibacterial activity of cefazolin against E. coli cell expressing VIM-2, resulting in a 4–8-fold reduction in MICs. The isothermal titration calorimetry (ITC) characterization suggested that the primary binding 2-triazolylthioacetamide (1b, 1c, or 1h) to VIM-2 was a combination of entropy and enthalpy contributions. Further, the crystal structure of VIM-2 in complex with 1b was obtained by co-crystallization with a hanging-drop vapour-diffusion method. The crystal structure analysis revealed that 1b bound to two Zn(II) ions of the enzyme active sites, formed H-bound with Asn233 and structure water molecule, and interacted with the hydrophobic pocket of enzyme activity center utilizing hydrophobic moieties; especially for the phenyl of aromatic carboxyl which formed π-π stacking with active residue His263. These studies confirmed that aromatic carboxyl substituted 2-triazolylthioacetamides are the potent VIM-2 inhibitors scaffold and provided help to further optimize 2-triazolylthioacetamides as VIM-2 even or broad-spectrum MβLs inhibitors. Full article

(This article belongs to the Special Issue Beta-Lactamases: Sequence, Structure, Function, and Inhibition)

► Show Figures

Graphical abstract

14 pages, 1402 KiB

Open AccessFeature PaperArticle

Mutation S115T in IMP-Type Metallo-β-Lactamases Compensates for Decreased Expression Levels Caused by Mutation S119G

by Charles J. Zhang, Mohammad Faheem, Paulie Dang, Monica N. Morris, Pooja Kumar and Peter Oelschlaeger

Biomolecules 2019, 9(11), 724; https://doi.org/10.3390/biom9110724 - 11 Nov 2019

Cited by 7 | Viewed by 3924

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 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)

► Show Figures

Graphical abstract

13 pages, 3332 KiB

Open AccessCommunication

Dithiocarbamate as a Valuable Scaffold for the Inhibition of Metallo-β-Lactmases

by Ying Ge, Li-Wei Xu, Ya Liu, Le-Yun Sun, Han Gao, Jia-Qi Li and Kewu Yang

Biomolecules 2019, 9(11), 699; https://doi.org/10.3390/biom9110699 - 5 Nov 2019

Cited by 17 | Viewed by 2410

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 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)

► Show Figures

Figure 1

18 pages, 459 KiB

Open AccessArticle

by Eva-Maria Saliu, Marita Eitinger, Jürgen Zentek and Wilfried Vahjen

Biomolecules 2019, 9(8), 324; https://doi.org/10.3390/biom9080324 - 31 Jul 2019

Cited by 7 | Viewed by 3013

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 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)

► Show Figures

Figure 1

Review

Jump to: Editorial, Research

35 pages, 3462 KiB

Open AccessReview

Metallo-β-Lactamase Inhibitors Inspired on Snapshots from the Catalytic Mechanism

by Antonela R. Palacios, María-Agustina Rossi, Graciela S. Mahler and Alejandro J. Vila

Biomolecules 2020, 10(6), 854; https://doi.org/10.3390/biom10060854 - 3 Jun 2020

Cited by 48 | Viewed by 9721

Abstract

β-Lactam antibiotics are the most widely prescribed antibacterial drugs due to their low toxicity and broad spectrum. Their action is counteracted by different resistance mechanisms developed by bacteria. Among them, the most common strategy is the expression of β-lactamases, enzymes that hydrolyze the amide bond present in all β-lactam compounds. There are several inhibitors against serine-β-lactamases (SBLs). Metallo-β-lactamases (MBLs) are Zn(II)-dependent enzymes able to hydrolyze most β-lactam antibiotics, and no clinically useful inhibitors against them have yet been approved. Despite their large structural diversity, MBLs have a common catalytic mechanism with similar reaction species. Here, we describe a number of MBL inhibitors that mimic different species formed during the hydrolysis process: substrate, transition state, intermediate, or product. Recent advances in the development of boron-based and thiol-based inhibitors are discussed in the light of the mechanism of MBLs. We also discuss the use of chelators as a possible strategy, since Zn(II) ions are essential for substrate binding and catalysis. Full article

(This article belongs to the Special Issue Beta-Lactamases: Sequence, Structure, Function, and Inhibition)

► Show Figures

Figure 1

32 pages, 1311 KiB

Open AccessEditor’s ChoiceReview

Carbapenemases: Transforming Acinetobacter baumannii into a Yet More Dangerous Menace

by Maria Soledad Ramirez, Robert A. Bonomo and Marcelo E. Tolmasky

Biomolecules 2020, 10(5), 720; https://doi.org/10.3390/biom10050720 - 6 May 2020

Cited by 120 | Viewed by 11733

Abstract

Acinetobacter baumannii is a common cause of serious nosocomial infections. Although community-acquired infections are observed, the vast majority occur in people with preexisting comorbidities. A. baumannii emerged as a problematic pathogen in the 1980s when an increase in virulence, difficulty in treatment due to drug resistance, and opportunities for infection turned it into one of the most important threats to human health. Some of the clinical manifestations of A. baumannii nosocomial infection are pneumonia; bloodstream infections; lower respiratory tract, urinary tract, and wound infections; burn infections; skin and soft tissue infections (including necrotizing fasciitis); meningitis; osteomyelitis; and endocarditis. A. baumannii has an extraordinary genetic plasticity that results in a high capacity to acquire antimicrobial resistance traits. In particular, acquisition of resistance to carbapenems, which are among the antimicrobials of last resort for treatment of multidrug infections, is increasing among A. baumannii strains compounding the problem of nosocomial infections caused by this pathogen. It is not uncommon to find multidrug-resistant (MDR, resistance to at least three classes of antimicrobials), extensively drug-resistant (XDR, MDR plus resistance to carbapenems), and pan-drug-resistant (PDR, XDR plus resistance to polymyxins) nosocomial isolates that are hard to treat with the currently available drugs. In this article we review the acquired resistance to carbapenems by A. baumannii. We describe the enzymes within the OXA, NDM, VIM, IMP, and KPC groups of carbapenemases and the coding genes found in A. baumannii clinical isolates. Full article

(This article belongs to the Special Issue Beta-Lactamases: Sequence, Structure, Function, and Inhibition)

► Show Figures

Figure 1

16 pages, 2761 KiB

Open AccessReview

The Role of the Ω-Loop in Regulation of the Catalytic Activity of TEM-Type β-Lactamases

by Alexey Egorov, Maya Rubtsova, Vitaly Grigorenko, Igor Uporov and Alexander Veselovsky

Biomolecules 2019, 9(12), 854; https://doi.org/10.3390/biom9120854 - 11 Dec 2019

Cited by 23 | Viewed by 4672

Abstract

Bacterial resistance to β-lactams, the most commonly used class of antibiotics, poses a global challenge. This resistance is caused by the production of bacterial enzymes that are termed β-lactamases (βLs). The evolution of serine-class A β-lactamases from penicillin-binding proteins (PBPs) is related to the formation of the Ω-loop at the entrance to the enzyme’s active site. In this loop, the Glu166 residue plays a key role in the two-step catalytic cycle of hydrolysis. This residue in TEM–type β-lactamases, together with Asn170, is involved in the formation of a hydrogen bonding network with a water molecule, leading to the deacylation of the acyl–enzyme complex and the hydrolysis of the β-lactam ring of the antibiotic. The activity exhibited by the Ω-loop is attributed to the positioning of its N-terminal residues near the catalytically important residues of the active site. The structure of the Ω-loop of TEM-type β-lactamases is characterized by low mutability, a stable topology, and structural flexibility. All of the revealed features of the Ω-loop, as well as the mechanisms related to its involvement in catalysis, make it a potential target for novel allosteric inhibitors of β-lactamases. Full article

(This article belongs to the Special Issue Beta-Lactamases: Sequence, Structure, Function, and Inhibition)

► Show Figures

Graphical abstract

Journal Menu

Journal Browser

Beta-Lactamases: Sequence, Structure, Function, and Inhibition

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Published Papers (14 papers)

Editorial

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI