Special Issue "Targeting β-lactamases to Fight Bacterial Resistance to β-lactam Antibiotics"

A special issue of Antibiotics (ISSN 2079-6382).

Deadline for manuscript submissions: closed (29 February 2020).

Special Issue Editor

Dr. Cecilia Pozzi
E-Mail Website
Guest Editor
Department of Biotechnology, Chemistry and Pharmacy, University of Siena, via Aldo Moro 2, 53100 Siena, Italy
Interests: X-ray crystallography; structural biology; β-lactamases; antibiotic resistance; bacterial thymidylate synthase; human thymidylate synthase; pteridine reductase; heat shock protein 90 N-terminal domain; bioinorganic chemistry; ferritin; glutaminyl cyclase
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

In bacteria, a major resistance mechanism to β-lactam antibiotics is represented by the production of one or more β-lactamase enzymes. β-Lactamases belong to two structurally and mechanistically unrelated families of enzymes, the serine-β-lactamases (SBLs; classes A, C, and D) and the metallo-β-lactamases (MBLs; class B). Recently, there has been renewed interest in discovering novel inhibitors to counter the threat from newer β-lactamases, such as the extended spectrum β-lactamases (ESBLs) and carbapenemases, which are not inhibited by the classical SBL inhibitors clavulanic acid and tazobactam. Two new SBL inhibitors, the diazabicyclooctane (DBO) avibactam and the boronate vaborbactam, which are used in combination with ceftazidime and meropenem, respectively, have been recently developed. However, as of yet, there are no MBL inhibitors in clinical use despite there being a clear unmet medical need.

This Special Issue features multidisciplinary research focused on β-lactamase enzymes to provide new insight into these key targets to fight bacteria resistance to β-lactam antibiotics. The main topics covered by this Special Issue are the identification and characterization of serine- and metallo-β-lactamase enzymes, mechanistic and structural studies, and the identification and development of SBL and MBL inhibitors.

Dr. Cecilia Pozzi
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 papers will be 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. Antibiotics 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 1800 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

  • serine-β-lactamases
  • metallo-β-lactamases
  • resistance
  • β-lactam antibiotics
  • β-lactamase inhibitors
  • extended spectrum β-lactamases
  • carbapenemases

Published Papers (11 papers)

Order results
Result details
Select all
Export citation of selected articles as:

Editorial

Jump to: Research, Review, Other

Editorial
Editorial for the Special Issue: “Targeting β-Lactamases to Fight Bacterial Resistance to β-Lactam Antibiotics”
Antibiotics 2020, 9(6), 290; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics9060290 - 28 May 2020
Viewed by 1072
Abstract
In bacteria, a major resistance mechanism to β-lactam antibiotics is the production of one or more β-lactamase enzymes [...] Full article

Research

Jump to: Editorial, Review, Other

Article
Isonitrile-Based Multicomponent Synthesis of β-Amino Boronic Acids as β-Lactamase Inhibitors
Antibiotics 2020, 9(5), 249; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics9050249 - 12 May 2020
Cited by 2 | Viewed by 1287
Abstract
The application of various isonitrile-based multicomponent reactions to protected (2-oxoethyl)boronic acid (as the carbonyl component) is described. The Ugi reaction, both in the four components and in the four centers–three components versions, and the van Leusen reaction, proved effective at providing small libraries [...] Read more.
The application of various isonitrile-based multicomponent reactions to protected (2-oxoethyl)boronic acid (as the carbonyl component) is described. The Ugi reaction, both in the four components and in the four centers–three components versions, and the van Leusen reaction, proved effective at providing small libraries of MIDA-protected β-aminoboronic acids. The corresponding free β-aminoboronic acids, quantitatively recovered through basic mild deprotection, were found to be quite stable and were fully characterized, including by 11B-NMR spectroscopy. Single-crystal X-ray diffraction analysis, applied both to a MIDA-protected and a free β-aminoboronic acid derivative, provided evidence for different conformations in the solid-state. Finally, the antimicrobial activities of selected compounds were evaluated by measuring their minimal inhibitory concentration (MIC) values, and the binding mode of the most promising derivative on OXA-23 class D β-lactamase was predicted by a molecular modeling study. Full article
Show Figures

Graphical abstract

Communication
Synthesis and Bioactivity of Thiazolethioacetamides as Potential Metallo-β-Lactamase Inhibitors
Antibiotics 2020, 9(3), 99; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics9030099 - 26 Feb 2020
Cited by 1 | Viewed by 976
Abstract
Metallo-β-lactamase (MβLs) mediated antibiotic resistance seriously threatens the treatment of bacterial diseases. Recently, we found that thioacetamides can be a potential MβL inhibitor skeleton. In order to improve the information of the skeleton, twelve new thiazolethioacetamides were designed by modifying the aromatic substituent. [...] Read more.
Metallo-β-lactamase (MβLs) mediated antibiotic resistance seriously threatens the treatment of bacterial diseases. Recently, we found that thioacetamides can be a potential MβL inhibitor skeleton. In order to improve the information of the skeleton, twelve new thiazolethioacetamides were designed by modifying the aromatic substituent. Biological activity assays identify the thiazolethioacetamides can inhibit ImiS with IC50 values of 0.17 to 0.70 μM. For two of them, the IC50 values against VIM-2 were 2.2 and 19.2 μM, which is lower than in our previous report. Eight of the thiazolethioacetamides are able to restore antibacterial activity of cefazolin against E.coli-ImiS by 2–4 fold. An analysis of the structure–activity relation and molecule docking show that the style and position of electron withdrawing groups in aromatic substituents play a crucial role in the inhibitory activity of thiazolethioacetamides. These results indicate that thiazolethioacetamides can serve as a potential skeleton of MβL inhibitors. Full article
Show Figures

Figure 1

Article
Phenylboronic Acids Probing Molecular Recognition against Class A and Class C β-lactamases
Antibiotics 2019, 8(4), 171; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics8040171 - 30 Sep 2019
Cited by 4 | Viewed by 1706
Abstract
Worldwide dissemination of pathogens resistant to almost all available antibiotics represent a real problem preventing efficient treatment of infectious diseases. Among antimicrobial used in therapy, β-lactam antibiotics represent 40% thus playing a crucial role in the management of infections treatment. We report a [...] Read more.
Worldwide dissemination of pathogens resistant to almost all available antibiotics represent a real problem preventing efficient treatment of infectious diseases. Among antimicrobial used in therapy, β-lactam antibiotics represent 40% thus playing a crucial role in the management of infections treatment. We report a small series of phenylboronic acids derivatives (BAs) active against class A carbapenemases KPC-2 and GES-5, and class C cephalosporinases AmpC. The inhibitory profile of our BAs against class A and C was investigated by means of molecular docking, enzyme kinetics and X-ray crystallography. We were interested in the mechanism of recognition among class A and class C to direct the design of broad serine β-Lactamases (SBLs) inhibitors. Molecular modeling calculations vs GES-5 and crystallographic studies vs AmpC reasoned, respectively, the ortho derivative 2 and the meta derivative 3 binding affinity. The ability of our BAs to protect β-lactams from BLs hydrolysis was determined in biological assays conducted against clinical strains: Fractional inhibitory concentration index (FICI) tests confirmed their ability to be synergic with β-lactams thus restoring susceptibility to meropenem. Considering the obtained results and the lack of cytotoxicity, our derivatives represent validated probe for the design of SBLs inhibitors. Full article
Show Figures

Graphical abstract

Article
Characterization of a Carbapenem-Resistant Kluyvera Cryocrescens Isolate Carrying Blandm-1 from Hospital Sewage
Antibiotics 2019, 8(3), 149; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics8030149 - 16 Sep 2019
Cited by 5 | Viewed by 1424
Abstract
Carbapenem-resistant Enterobacteriaceae have been a global public health issue in recent years. Here, a carbapenem-resistant Kluyvera cryocrescens strain SCW13 was isolated from hospital sewage, and was then subjected to whole-genome sequencing (WGS). Based on WGS data, antimicrobial resistance genes were identified. Resistance plasmids [...] Read more.
Carbapenem-resistant Enterobacteriaceae have been a global public health issue in recent years. Here, a carbapenem-resistant Kluyvera cryocrescens strain SCW13 was isolated from hospital sewage, and was then subjected to whole-genome sequencing (WGS). Based on WGS data, antimicrobial resistance genes were identified. Resistance plasmids were completely circularized and further bioinformatics analyses of plasmids were performed. A conjugation assay was performed to identify a self-transmissible plasmid mediating carbapenem resistance. A phylogenetic tree was constructed based on the core genome of publicly available Kluyvera strains. The isolate SCW13 exhibited resistance to cephalosporin and carbapenem. blaNDM-1 was found to be located on a ~53-kb self-transmissible IncX3 plasmid, which exhibited high similarity to the previously reported pNDM-HN380, which is an epidemic blaNDM-1-carrying IncX3 plasmid. Further, we found that SCW13 contained a chromosomal blaKLUC-2 gene, which was the probable origin of the plasmid-born blaKLUC-2 found in Enterobacter cloacae. Phylogenetic analysis showed that K. cryocrescens SCW13 exhibited a close relationship with K. cryocrescens NCTC10483. These findings highlight the further dissemination of blaNDM through clonal IncX3 plasmids related to pNDM-HN380 among uncommon Enterobacteriaceae strains, including Kluyvera in this case. Full article
Show Figures

Figure 1

Article
Structural Analysis of The OXA-48 Carbapenemase Bound to A “Poor” Carbapenem Substrate, Doripenem
Antibiotics 2019, 8(3), 145; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics8030145 - 11 Sep 2019
Cited by 5 | Viewed by 1678
Abstract
Carbapenem-resistant Enterobacteriaceae are a significant threat to public health, and a major resistance determinant that promotes this phenotype is the production of the OXA-48 carbapenemase. The activity of OXA-48 towards carbapenems is a puzzling phenotype as its hydrolytic activity against doripenem is non-detectable. [...] Read more.
Carbapenem-resistant Enterobacteriaceae are a significant threat to public health, and a major resistance determinant that promotes this phenotype is the production of the OXA-48 carbapenemase. The activity of OXA-48 towards carbapenems is a puzzling phenotype as its hydrolytic activity against doripenem is non-detectable. To probe the mechanistic basis for this observation, we determined the 1.5 Å resolution crystal structure of the deacylation deficient K73A variant of OXA-48 in complex with doripenem. Doripenem is observed in the Δ1R and Δ1S tautomeric states covalently attached to the catalytic S70 residue. Likely due to positioning of residue Y211, the carboxylate moiety of doripenem is making fewer hydrogen bonding/salt-bridge interactions with R250 compared to previously determined carbapenem OXA structures. Moreover, the hydroxyethyl side chain of doripenem is making van der Waals interactions with a key V120 residue, which likely affects the deacylation rate of doripenem. We hypothesize that positions V120 and Y211 play important roles in the carbapenemase profile of OXA-48. Herein, we provide insights for the further development of the carbapenem class of antibiotics that could render them less effective to hydrolysis by or even inhibit OXA carbapenemases. Full article
Show Figures

Figure 1

Review

Jump to: Editorial, Research, Other

Review
The Current Burden of Carbapenemases: Review of Significant Properties and Dissemination among Gram-Negative Bacteria
Antibiotics 2020, 9(4), 186; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics9040186 - 16 Apr 2020
Cited by 20 | Viewed by 1824
Abstract
Carbapenemases are β-lactamases belonging to different Ambler classes (A, B, D) and can be encoded by both chromosomal and plasmid-mediated genes. These enzymes represent the most potent β-lactamases, which hydrolyze a broad variety of β-lactams, including carbapenems, cephalosporins, penicillin, and aztreonam. The major [...] Read more.
Carbapenemases are β-lactamases belonging to different Ambler classes (A, B, D) and can be encoded by both chromosomal and plasmid-mediated genes. These enzymes represent the most potent β-lactamases, which hydrolyze a broad variety of β-lactams, including carbapenems, cephalosporins, penicillin, and aztreonam. The major issues associated with carbapenemase production are clinical due to compromising the activity of the last resort antibiotics used for treating serious infections, and epidemiological due to their dissemination into various bacteria across almost all geographic regions. Carbapenemase-producing Enterobacteriaceae have received more attention upon their first report in the early 1990s. Currently, there is increased awareness of the impact of nonfermenting bacteria, such as Acinetobacter baumannii and Pseudomonas aeruginosa, as well as other Gram-negative bacteria that are carbapenemase-producers. Outside the scope of clinical importance, carbapenemases are also detected in bacteria from environmental and zoonotic niches, which raises greater concerns over their prevalence, and the need for public health measures to control consequences of their propagation. The aims of the current review are to define and categorize the different families of carbapenemases, and to overview the main lines of their spread across different bacterial groups. Full article
Show Figures

Figure 1

Review
Insights into Acinetobacter baumannii: A Review of Microbiological, Virulence, and Resistance Traits in a Threatening Nosocomial Pathogen
Antibiotics 2020, 9(3), 119; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics9030119 - 12 Mar 2020
Cited by 34 | Viewed by 3137
Abstract
Being a multidrug-resistant and an invasive pathogen, Acinetobacter baumannii is one of the major causes of nosocomial infections in the current healthcare system. It has been recognized as an agent of pneumonia, septicemia, meningitis, urinary tract and wound infections, and is associated with [...] Read more.
Being a multidrug-resistant and an invasive pathogen, Acinetobacter baumannii is one of the major causes of nosocomial infections in the current healthcare system. It has been recognized as an agent of pneumonia, septicemia, meningitis, urinary tract and wound infections, and is associated with high mortality. Pathogenesis in A. baumannii infections is an outcome of multiple virulence factors, including porins, capsules, and cell wall lipopolysaccharide, enzymes, biofilm production, motility, and iron-acquisition systems, among others. Such virulence factors help the organism to resist stressful environmental conditions and enable development of severe infections. Parallel to increased prevalence of infections caused by A. baumannii, challenging and diverse resistance mechanisms in this pathogen are well recognized, with major classes of antibiotics becoming minimally effective. Through a wide array of antibiotic-hydrolyzing enzymes, efflux pump changes, impermeability, and antibiotic target mutations, A. baumannii models a unique ability to maintain a multidrug-resistant phenotype, further complicating treatment. Understanding mechanisms behind diseases, virulence, and resistance acquisition are central to infectious disease knowledge about A. baumannii. The aims of this review are to highlight infections and disease-producing factors in A. baumannii and to touch base on mechanisms of resistance to various antibiotic classes. Full article
Show Figures

Figure 1

Other

Brief Report
Ceftazidime–Avibactam versus Meropenem for the Treatment of Complicated Intra-Abdominal Infections
Antibiotics 2019, 8(4), 255; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics8040255 - 06 Dec 2019
Cited by 5 | Viewed by 1595
Abstract
This study reports an integrated analysis of three randomized controlled trials to compare the clinical efficacies and safety of the ceftazidime–avibactam (CAZ–AVI) combination and meropenem in the treatment of adult patients with complicated intra-abdominal infections (cIAIs). Overall, a total of 1677 patients (CAZ–AVI: [...] Read more.
This study reports an integrated analysis of three randomized controlled trials to compare the clinical efficacies and safety of the ceftazidime–avibactam (CAZ–AVI) combination and meropenem in the treatment of adult patients with complicated intra-abdominal infections (cIAIs). Overall, a total of 1677 patients (CAZ–AVI: 835 patients; meropenem: 842 patients) were included in this analysis. CAZ–AVI had a clinical cure rate at test of cure in the clinically evaluable (CE) population similar to that of meropenem (OR, 0.88; 95% CI, 0.58–1.32; I2 = 0%). Similar trends were also observed in the modified intent-to-treat (MITT) population (OR, 0.80; 95% CI, 0.59–1.09; I2 = 0%) and microbiological evaluable (ME) population (OR, 0.73; 95% CI, 0.32–1.68; I2 = 0%). In terms of clinical cure rate at the end of treatment, the efficacy of CAZ–AVI was comparable to that of meropenem in the CE population (OR, 0.77; 95% CI, 0.47–1.25; I2 = 0%), MITT population (OR, 0.70; 95% CI, 0.47–1.06; I2 = 5%), and ME population (OR, 1.26; 95% CI, 0.39–4.08; I2 = 0%). CAZ–AVI had a similar risk of (i) treatment emergent adverse events (TEAEs) (OR, 1.03; 95% CI, 0.79–1.36; I2 = 38%), (ii) any serious adverse events (OR, 0.97; 95% CI, 0.67–1.40; I2 = 0%), (iii) discontinuation of study drug due to TEAE (OR, 2.14; 95% CI, 1.00–4.57), and iv) all-cause mortality (OR, 1.66; 95% CI, 0.78–3.53; I2 = 0%) when compared with meropenem. In conclusion, CAZ–AVI had comparable efficacy and safety profile to those of meropenem in the treatment of cIAI. Full article
Show Figures

Figure 1

Brief Report
Novel β-Lactam/β-Lactamase Combination Versus Meropenem for Treating Nosocomial Pneumonia
Antibiotics 2019, 8(4), 219; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics8040219 - 13 Nov 2019
Cited by 2 | Viewed by 1708
Abstract
This study reports the integrated analysis of two phase III studies of novel β-lactam/β-lactamase combination versus meropenem for treating nosocomial pneumonia (NP) including ventilator-associated pneumonia (VAP). The ASPECT-NP trial compared the efficacy and safety of ceftolozane–tazobactam versus meropenem for treating NP/VAP. The REPROVE [...] Read more.
This study reports the integrated analysis of two phase III studies of novel β-lactam/β-lactamase combination versus meropenem for treating nosocomial pneumonia (NP) including ventilator-associated pneumonia (VAP). The ASPECT-NP trial compared the efficacy and safety of ceftolozane–tazobactam versus meropenem for treating NP/VAP. The REPROVE trial compared ceftazidime–avibactam and meropenem in the treatment of NP/VAP. A total of 1528 patients (361 in the ceftolozane–tazobactam group; 405 in the ceftazidime–avibactam group; 762 in the meropenem group) were analyzed. The clinical cure rates at test-of-cure among the novel β-lactam/β-lactamase combinations group were non-inferior to those of the meropenem (70.7% vs. 72.1%, risk difference (RD) −0.01, 95% confidence interval (CI) 0.06–0.05) in the clinical evaluable populations. Overall 28-day mortality did not differ between novel β-lactam/β-lactamase combinations and the meropenem group (RD, −0.02, 95% CI, −0.09 to 0.05). Regarding the microbiological eradication rate, novel β-lactam/β-lactamase combinations were non-inferior to meropenem for Pseudomonas aeruginosa, Klebsiella pneumoniae, Proteus mirabilis, Haemophilus influenzae, Staphylococcus marcescens, and Enterobacter cloacae. Finally, novel β-lactam/β-lactamase combinations had a similar risk of (i) treatment-emergent adverse events (RD, 0.02, 95% CI, −0.02 to 0.06), (ii) events leading to the discontinuation of the study drug (RD, 0.00, 95% CI, −0.02 to 0.03), (iii) severe adverse events (RD, 0.03, 95% CI, −0.01 to 0.07), and (iv) death (RD, 0.02, 95% CI, −0.02 to 0.05) when compared with meropenem group. In conclusion, our findings suggest that novel β-lactam/β-lactamase combinations of ceftolozane−tazobactam and ceftazidime–avibactam can be recommended as one of the therapeutic options in the treatment of NP/VAP. Full article
Show Figures

Figure 1

Letter
Stability of Biological Activity of Frozen β-lactams over Time as Assessed by Time-Lapsed Broth Microdilutions
Antibiotics 2019, 8(4), 165; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics8040165 - 25 Sep 2019
Cited by 2 | Viewed by 1256
Abstract
To evaluate the antimicrobial agent’s stability stored at −80 °C, six β-lactams (meropenem, ertapenem, imipenem, ceftriaxone, ceftazidime, and piperacillin-tazobactam) were studied using the broth microdilution (BMD). The minimum inhibitory concentration (MIC) remained accurate with the same amount of frozen drug for at least [...] Read more.
To evaluate the antimicrobial agent’s stability stored at −80 °C, six β-lactams (meropenem, ertapenem, imipenem, ceftriaxone, ceftazidime, and piperacillin-tazobactam) were studied using the broth microdilution (BMD). The minimum inhibitory concentration (MIC) remained accurate with the same amount of frozen drug for at least six months. Thereafter, there was a diminishing drug concentration due to instability. At this temperature, most β-lactams can be frozen as a stock concentration for up to six months without a significant loss in antibiotic activity. Full article
Back to TopTop