Feature Review Papers on β-Lactam and β-Lactam-β-Lactamase Inhibitor Combinations and Resistance Mechanisms to β-Lactam and β-Lactam-β-Lactamase Inhibitor Combinations

A special issue of Antibiotics (ISSN 2079-6382). This special issue belongs to the section "Mechanism and Evolution of Antibiotic Resistance".

Deadline for manuscript submissions: closed (31 October 2023) | Viewed by 10405

Special Issue Editors


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Operations Manager, JMI Laboratories, A Subsidiary of Element Materials Technology, 345 Beaver Kreek Center, Suite A, North Liberty, IA 52317, USA
Interests: serine β-lactamases, β-lactams; β-lactamase inhibitors; Burkholderia; carbapenem-resistant gram negatives; structure-activity relationships; enzyme kinetics; mass spectrometry
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Guest Editor
Department of Microbiology and Molecular Biology, CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology, Case Western Reserve University, Cleveland, OH, USA
Interests: metallo-β-lactamases; β-lactams; β-lactamase inhibitors; Stenotrophomonas; structure-activity relationships; enzyme kinetics; mass spectrometry

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Guest Editor
Department of Chemistry, and the Stanford Synchrotron Radiation Lightsource (SSRL), Stanford University, Stanford, CA, USA
Interests: structural studies on mechanisms of resistance to β-lactam antibiotics and inhibitors; serine β-lactamases

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Guest Editor
School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK
Interests: structural studies on mechanisms of resistance to β-lactam antibiotics and inhibitors; serine and metallo-β-lactamases

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Guest Editor
Louis Stokes Cleveland VA Medical Center and Case Western Reserve University, Cleveland, OH, USA
Interests: mycobacterial infections; β-lactams; Gram negatives; Enterococci; dual β-lactams and β-lactamase inhibitors

Special Issue Information

Dear Colleagues,

The description of the topic:   β-Lactam and β-lactamase inhibitors are the safest and most commonly prescribed class of antibiotics. Over the last decade, great progress has been made in combating the emergence of β-lactam resistance in Gram-negative pathogens. Moreover, highly β-lactam-resistant pathogens continue to emerge in the clinic, challenging our current diagnostics as well as treatment strategies. The goal of this Special Issue is to gather the world’s leading experts in the field and provide the readership with a collection of focused review articles regarding these topics. Review articles regarding β-lactam agents, resistance mechanisms that lead to β-lactam resistance, as well as reviews concerning clinical challenges and diagnostic tools are welcomed.

Dr. Krisztina M. Papp-Wallace
Dr. Maria Fernanda Mojica
Dr. Clyde Smith
Dr. Philip Hinchliffe
Dr. Khalid Dousa
Guest Editors

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Keywords

  • β-lactamase
  • β-lactam
  • β-lactamase inhibitor
  • Gram-negatives
  • resistance mechanisms
  • clinical challenges
  • penicillin binding proteins
  • porins
  • outer membrane vesicles
  • diagnostics
  • antibiotic stewardship

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Published Papers (3 papers)

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Review

25 pages, 4639 KiB  
Review
Drug Discovery in the Field of β-Lactams: An Academic Perspective
by Lian M. C. Jacobs, Patrick Consol and Yu Chen
Antibiotics 2024, 13(1), 59; https://doi.org/10.3390/antibiotics13010059 - 8 Jan 2024
Cited by 7 | Viewed by 4453
Abstract
β-Lactams are the most widely prescribed class of antibiotics that inhibit penicillin-binding proteins (PBPs), particularly transpeptidases that function in peptidoglycan synthesis. A major mechanism of antibiotic resistance is the production of β-lactamase enzymes, which are capable of hydrolyzing β-lactam antibiotics. There have been [...] Read more.
β-Lactams are the most widely prescribed class of antibiotics that inhibit penicillin-binding proteins (PBPs), particularly transpeptidases that function in peptidoglycan synthesis. A major mechanism of antibiotic resistance is the production of β-lactamase enzymes, which are capable of hydrolyzing β-lactam antibiotics. There have been many efforts to counter increasing bacterial resistance against β-lactams. These studies have mainly focused on three areas: discovering novel inhibitors against β-lactamases, developing new β-lactams less susceptible to existing resistance mechanisms, and identifying non-β-lactam inhibitors against cell wall transpeptidases. Drug discovery in the β-lactam field has afforded a range of research opportunities for academia. In this review, we summarize the recent new findings on both β-lactamases and cell wall transpeptidases because these two groups of enzymes are evolutionarily and functionally connected. Many efforts to develop new β-lactams have aimed to inhibit both transpeptidases and β-lactamases, while several promising novel β-lactamase inhibitors have shown the potential to be further developed into transpeptidase inhibitors. In addition, the drug discovery progress against each group of enzymes is presented in three aspects: understanding the targets, screening methodology, and new inhibitor chemotypes. This is to offer insights into not only the advancement in this field but also the challenges, opportunities, and resources for future research. In particular, cyclic boronate compounds are now capable of inhibiting all classes of β-lactamases, while the diazabicyclooctane (DBO) series of small molecules has led to not only new β-lactamase inhibitors but potentially a new class of antibiotics by directly targeting PBPs. With the cautiously optimistic successes of a number of new β-lactamase inhibitor chemotypes and many questions remaining to be answered about the structure and function of cell wall transpeptidases, non-β-lactam transpeptidase inhibitors may usher in the next exciting phase of drug discovery in this field. Full article
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21 pages, 1573 KiB  
Review
Strategies to Name Metallo-β-Lactamases and Number Their Amino Acid Residues
by Peter Oelschlaeger, Heba Kaadan and Rinku Dhungana
Antibiotics 2023, 12(12), 1746; https://doi.org/10.3390/antibiotics12121746 - 16 Dec 2023
Viewed by 2197
Abstract
Metallo-β-lactamases (MBLs), also known as class B β-lactamases (BBLs), are Zn(II)-containing enzymes able to inactivate a broad range of β-lactams, the most commonly used antibiotics, including life-saving carbapenems. They have been known for about six decades, yet they have only gained much attention [...] Read more.
Metallo-β-lactamases (MBLs), also known as class B β-lactamases (BBLs), are Zn(II)-containing enzymes able to inactivate a broad range of β-lactams, the most commonly used antibiotics, including life-saving carbapenems. They have been known for about six decades, yet they have only gained much attention as a clinical problem for about three decades. The naming conventions of these enzymes have changed over time and followed various strategies, sometimes leading to confusion. We are summarizing the naming strategies of the currently known MBLs. These enzymes are quite diverse on the amino acid sequence level but structurally similar. Problems trying to describe conserved residues, such as Zn(II) ligands and other catalytically important residues, which have different numbers in different sequences, have led to the establishment of a standard numbering scheme for BBLs. While well intended, the standard numbering scheme is not trivial and has not been applied consistently. We revisit this standard numbering scheme and suggest some strategies for how its implementation could be made more accessible to researchers. Standard numbering facilitates the comparison of different enzymes as well as their interaction with novel antibiotics and BBL inhibitors. Full article
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17 pages, 320 KiB  
Review
Approaches to Testing Novel β-Lactam and β-Lactam Combination Agents in the Clinical Laboratory
by Carmella Russo and Romney Humphries
Antibiotics 2023, 12(12), 1700; https://doi.org/10.3390/antibiotics12121700 - 5 Dec 2023
Cited by 2 | Viewed by 2957
Abstract
The rapid emergence of multi-drug resistant Gram-negative pathogens has driven the introduction of novel β-lactam combination agents (BLCs) to the antibiotic market: ceftolozane-tazobactam, ceftazidime-avibactam, meropenem-vaborbactam, imipenem-relebactam, cefiderocol, and sulbactam-durlobactam. These agents are equipped with innovative mechanisms that confer broad Gram-negative activity, notably against [...] Read more.
The rapid emergence of multi-drug resistant Gram-negative pathogens has driven the introduction of novel β-lactam combination agents (BLCs) to the antibiotic market: ceftolozane-tazobactam, ceftazidime-avibactam, meropenem-vaborbactam, imipenem-relebactam, cefiderocol, and sulbactam-durlobactam. These agents are equipped with innovative mechanisms that confer broad Gram-negative activity, notably against certain challenging carbapenemases. While their introduction offers a beacon of hope, clinical microbiology laboratories must navigate the complexities of susceptibility testing for these agents due to their diverse activity profiles against specific β-lactamases and the possibility of acquired resistance mechanisms in some bacterial isolates. This review explores the complexities of these novel antimicrobial agents detailing the intricacies of their application, providing guidance on the nuances of susceptibility testing, interpretation, and result reporting in clinical microbiology laboratories. Full article
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