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New Beta-Lactams, Beta-Lactamase Inhibitors and Targets for Beta-Lactamase Production Blockade: Powerful Allies against Multidrug-Resistant Pathogens 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Microbiology".

Deadline for manuscript submissions: closed (31 July 2022) | Viewed by 19942

Special Issue Editor

Dr. Carlos Juan Nicolau

E-Mail Website
Guest Editor
Hospital Universitari Son Espases- Health Research Institute of the Balearic Islands (IdISBa), Palma, Spain
Interests: nosocomial gram-negative pathogens; antibiotic resistance; peptidoglycan biology; host-pathogen interaction; virulence; cell-wall-targeting immunity
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Antibiotic resistance, especially referred to nosocomial opportunistic bacterial pathogens, is already an undeniable threat for public health worldwide, with obvious clinical and economic consequences. In the specific context of beta-lactam antibiotics, the threat is certainly not less severe, given their generalized use. Nevertheless, the appearance of new therapeutic options brings us a reason for hope. Among these therapeutic allies, we acknowledge: (i) the appearance of novel beta-lactam-related drugs (such as cefiderocol or ceftobiprole); (ii) the use of new antibiotic combinations including beta-lactamase activity inhibitors (for instance ceftazidime/avibactam, ceftolozane/tazobactam, imipenem/relebactam, and meropenem-vaborbactam), and (iii) the research on unexplored targets leading to the blockade of intrinsic beta-lactamases production (usually related to cell wall metabolism, such as AmpG or NagZ proteins, which have been shown to be essential for the correct expression of intrinsic beta-lactamases and full virulence in Pseudomonas aeruginosa and related species). Reviews and research papers related to these topics (referring to either Gram-positive or Gram-negative pathogens), but also those about novel characterizations of acquired/intrinsic Beta-lactamases are welcome for this Special Issue.

Dr. Carlos Juan Nicolau
Guest Editor

Manuscript Submission Information

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Keywords

  • Antibiotic resistance
  • ESKAPE pathogens
  • MRSA
  • Enterobacteriaceae
  • Acinetobacter baumannii
  • Pseudomonas aeruginosa
  • horizontally acquired beta-lactamases
  • carbapenemases
  • beta-lactamase inhibitors
  • intrinsic beta-lactamases
  • peptidoglycan recycling
  • cell wall metabolism
  • virulence
  • AmpC cephalosporinase
  • Cefiderocol
  • Ceftobiprole
  • ceftazidime/avibactam
  • ceftolozane/tazobactam
  • imipenem/relebactam
  • meropenem/vaborbactam

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Related Special Issue

Published Papers (4 papers)

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Research

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19 pages, 3126 KiB  
Article
Characterization of Interactions between CTX-M-15 and Clavulanic Acid, Desfuroylceftiofur, Ceftiofur, Ampicillin, and Nitrocefin
by Parvaneh Ahmadvand, Johannetsy J. Avillan, Jacob A. Lewis, Douglas R. Call and ChulHee Kang
Int. J. Mol. Sci. 2022, 23(9), 5229; https://doi.org/10.3390/ijms23095229 - 7 May 2022
Cited by 9 | Viewed by 2678
Abstract
Cefotaximase-Munich (CTX-M) extended-spectrum beta-lactamases (ESBLs) are commonly associated with Gram-negative, hospital-acquired infections worldwide. Several beta-lactamase inhibitors, such as clavulanate, are used to inhibit the activity of these enzymes. To understand the mechanism of CTX-M-15 activity, we have determined the crystal structures of CTX-M-15 [...] Read more.
Cefotaximase-Munich (CTX-M) extended-spectrum beta-lactamases (ESBLs) are commonly associated with Gram-negative, hospital-acquired infections worldwide. Several beta-lactamase inhibitors, such as clavulanate, are used to inhibit the activity of these enzymes. To understand the mechanism of CTX-M-15 activity, we have determined the crystal structures of CTX-M-15 in complex with two specific classes of beta-lactam compounds, desfuroylceftiofur (DFC) and ampicillin, and an inhibitor, clavulanic acid. The crystal structures revealed that Ser70 and five other residues (Lys73, Tyr105, Glu166, Ser130, and Ser237) participate in catalysis and binding of those compounds. Based on analysis of steady-state kinetics, thermodynamic data, and molecular docking to both wild-type and S70A mutant structures, we determined that CTX-M-15 has a similar affinity for all beta-lactam compounds (ceftiofur, nitrocefin, DFC, and ampicillin), but with lower affinity for clavulanic acid. A catalytic mechanism for tested β-lactams and two-step inhibition mechanism of clavulanic acid were proposed. CTX-M-15 showed a higher activity toward DFC and nitrocefin, but significantly lower activity toward ampicillin and ceftiofur. The interaction between CTX-M-15 and both ampicillin and ceftiofur displayed a higher entropic but lower enthalpic effect, compared with DFC and nitrocefin. DFC, a metabolite of ceftiofur, displayed lower entropy and higher enthalpy than ceftiofur. This finding suggests that compounds containing amine moiety (e.g., ampicillin) and the furfural moiety (e.g., ceftiofur) could hinder the hydrolytic activity of CTX-M-15. Full article
(This article belongs to the Special Issue New Beta-Lactams, Beta-Lactamase Inhibitors and Targets for Beta-Lactamase Production Blockade: Powerful Allies against Multidrug-Resistant Pathogens 2.0)
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26 pages, 3599 KiB  
Article
Synthesis of 3-Amino-4-substituted Monocyclic ß-Lactams—Important Structural Motifs in Medicinal Chemistry
by Katarina Grabrijan, Nika Strašek and Stanislav Gobec
Int. J. Mol. Sci. 2022, 23(1), 360; https://doi.org/10.3390/ijms23010360 - 29 Dec 2021
Cited by 5 | Viewed by 3694
Abstract
Monocyclic ß-lactams (azetidin-2-ones) exhibit a wide range of biological activities, the most important of which are antibacterial, anticancer, and cholesterol absorption inhibitory activities. The synthesis of decorated monocyclic ß-lactams is challenging because their ring is highly constrained and consequently reactive, which is also [...] Read more.
Monocyclic ß-lactams (azetidin-2-ones) exhibit a wide range of biological activities, the most important of which are antibacterial, anticancer, and cholesterol absorption inhibitory activities. The synthesis of decorated monocyclic ß-lactams is challenging because their ring is highly constrained and consequently reactive, which is also an important determinant of their biological activity. We present the optimized synthesis of orthogonally protected 3-amino-4-substituted monocyclic ß-lactams. Among several possible synthetic approaches, Staudinger cycloaddition proved to be the most promising method for initial ring formation, yielding monocyclic ß-lactams with different substituents at the C-4 position, a phthalimido-protected 3-amino group, and a (dimethoxy)benzyl protected ring nitrogen. Challenging deprotection methods were then investigated. Oxidative cleavage with cerium ammonium nitrate and ammonia-free Birch reduction was found to be most effective for selective removal of ring nitrogen protection. Hydrazine hydrate was used for deprotection of the phthalimido group, and the procedure had to be modified by the addition of HCl in the case of aromatic substituents at the C-4 position. The presented methods and the synthesized 3-amino-4-substituted monocyclic ß-lactam derivatives are an important step toward new ß-lactams with potential pharmacological activities. Full article
(This article belongs to the Special Issue New Beta-Lactams, Beta-Lactamase Inhibitors and Targets for Beta-Lactamase Production Blockade: Powerful Allies against Multidrug-Resistant Pathogens 2.0)
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29 pages, 6586 KiB  
Article
Rotating Magnetic Field Increases β-Lactam Antibiotic Susceptibility of Methicillin-Resistant Staphylococcus aureus Strains
by Marta Woroszyło, Daria Ciecholewska-Juśko, Adam Junka, Radosław Drozd, Marcin Wardach, Paweł Migdał, Patrycja Szymczyk-Ziółkowska, Daniel Styburski and Karol Fijałkowski
Int. J. Mol. Sci. 2021, 22(22), 12397; https://doi.org/10.3390/ijms222212397 - 17 Nov 2021
Cited by 9 | Viewed by 3880
Abstract
Methicillin-resistant strains of Staphylococcus aureus (MRSA) have developed resistance to most β-lactam antibiotics and have become a global health issue. In this work, we analyzed the impact of a rotating magnetic field (RMF) of well-defined and strictly controlled characteristics coupled with β-lactam antibiotics [...] Read more.
Methicillin-resistant strains of Staphylococcus aureus (MRSA) have developed resistance to most β-lactam antibiotics and have become a global health issue. In this work, we analyzed the impact of a rotating magnetic field (RMF) of well-defined and strictly controlled characteristics coupled with β-lactam antibiotics against a total of 28 methicillin-resistant and sensitive S. aureus strains. The results indicate that the application of RMF combined with β-lactam antibiotics correlated with favorable changes in growth inhibition zones or in minimal inhibitory concentrations of the antibiotics compared to controls unexposed to RMF. Fluorescence microscopy indicated a drop in the relative number of cells with intact cell walls after exposure to RMF. These findings were additionally supported by the use of SEM and TEM microscopy, which revealed morphological alterations of RMF-exposed cells manifested by change of shape, drop in cell wall density and cytoplasm condensation. The obtained results indicate that the originally limited impact of β-lactam antibiotics in MRSA is boosted by the disturbances caused by RMF in the bacterial cell walls. Taking into account the high clinical need for new therapeutic options, effective against MRSA, the data presented in this study have high developmental potential and could serve as a basis for new treatment options for MRSA infections. Full article
(This article belongs to the Special Issue New Beta-Lactams, Beta-Lactamase Inhibitors and Targets for Beta-Lactamase Production Blockade: Powerful Allies against Multidrug-Resistant Pathogens 2.0)
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Review

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18 pages, 914 KiB  
Review
Penicillin-Binding Proteins, β-Lactamases, and β-Lactamase Inhibitors in β-Lactam-Producing Actinobacteria: Self-Resistance Mechanisms
by Juan F. Martin, Ruben Alvarez-Alvarez and Paloma Liras
Int. J. Mol. Sci. 2022, 23(10), 5662; https://doi.org/10.3390/ijms23105662 - 18 May 2022
Cited by 9 | Viewed by 8540
Abstract
The human society faces a serious problem due to the widespread resistance to antibiotics in clinical practice. Most antibiotic biosynthesis gene clusters in actinobacteria contain genes for intrinsic self-resistance to the produced antibiotics, and it has been proposed that the antibiotic resistance genes [...] Read more.
The human society faces a serious problem due to the widespread resistance to antibiotics in clinical practice. Most antibiotic biosynthesis gene clusters in actinobacteria contain genes for intrinsic self-resistance to the produced antibiotics, and it has been proposed that the antibiotic resistance genes in pathogenic bacteria originated in antibiotic-producing microorganisms. The model actinobacteria Streptomyces clavuligerus produces the β-lactam antibiotic cephamycin C, a class A β-lactamase, and the β lactamases inhibitor clavulanic acid, all of which are encoded in a gene supercluster; in addition, it synthesizes the β-lactamase inhibitory protein BLIP. The secreted clavulanic acid has a synergistic effect with the cephamycin produced by the same strain in the fight against competing microorganisms in its natural habitat. High levels of resistance to cephamycin/cephalosporin in actinobacteria are due to the presence (in their β-lactam clusters) of genes encoding PBPs which bind penicillins but not cephalosporins. We have revised the previously reported cephamycin C and clavulanic acid gene clusters and, in addition, we have searched for novel β-lactam gene clusters in protein databases. Notably, in S. clavuligerus and Nocardia lactamdurans, the β-lactamases are retained in the cell wall and do not affect the intracellular formation of isopenicillin N/penicillin N. The activity of the β-lactamase in S. clavuligerus may be modulated by the β-lactamase inhibitory protein BLIP at the cell-wall level. Analysis of the β-lactam cluster in actinobacteria suggests that these clusters have been moved by horizontal gene transfer between different actinobacteria and have culminated in S. clavuligerus with the organization of an elaborated set of genes designed for fine tuning of antibiotic resistance and cell wall remodeling for the survival of this Streptomyces species. This article is focused specifically on the enigmatic connection between β-lactam biosynthesis and β-lactam resistance mechanisms in the producer actinobacteria. Full article
(This article belongs to the Special Issue New Beta-Lactams, Beta-Lactamase Inhibitors and Targets for Beta-Lactamase Production Blockade: Powerful Allies against Multidrug-Resistant Pathogens 2.0)
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