β-Lactams from the Ocean

Fisher, Jed F.; Mobashery, Shahriar

doi:10.3390/md21020086

Cited by 8 publications

(5 citation statements)

References 168 publications

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“…β-Lactones represent another new class of potential PBP inhibitors due to the chemical similarity between β-lactones and β-lactams [224]. These compounds have been used as chemical probes to selectively target specific PBPs in S. pneumoniae [225,226].…”

Section: New Transpeptidase Inhibitor Scaffoldsmentioning

confidence: 99%

Drug Discovery in the Field of β-Lactams: An Academic Perspective

Jacobs,

Consol,

Chen

2024

Antibiotics

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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.

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Section: New Transpeptidase Inhibitor Scaffoldsmentioning

confidence: 99%

Drug Discovery in the Field of β-Lactams: An Academic Perspective

Jacobs,

Consol,

Chen

2024

Antibiotics

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“…The nucleophilic attack on the latter leads to the formation of a tetrahedral intermediate, a species whose collapse results in acylation of the enzyme. This covalent binding of an amide/β-lactam with an enzyme has essential requirements, which have been extensively described in the literature [1,8,9].…”

Section: Lactams-cyclic Amidesmentioning

confidence: 99%

β-Lactams and Ureas as Cross Inhibitors of Prokaryotic Systems

Konaklieva

Plotkin

2023

Applied Microbiology

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β-Lactams in the last thirty years have been viewed as universal acylating agents of serine and cysteine enzymes of both prokaryotic and eukaryotic systems. More recently, their use has been propelled by the COVID-19 pandemic, thus broadening their application as inhibitors of viral enzymes. The urea-based drugs have been extensively studied as inhibitors of the aforementioned enzymes. The focus of this review is the last decade’s drug discovery strategies, as well as new strategies that show utility in the expansion of β-lactams and ureas in the development of new antimicrobial and antiviral drugs.

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“…Members of his class of compound are also indicated for the treatment of Parkinson's disease 1,2 . Because of increasing prevalence of antibiotic resistance, there is persistent interest in the evaluation of novel derivatives of this structural class and others to supplement the available penicillin, cephalosporin, and monobactam analogs now widely used to treat infections 3,4 . This continuing interest mandates a deeper understanding of the structural characteristics of the precursors to more complex variants.…”

Section: Introductionmentioning

confidence: 99%

DFT investigation of coupling constant anomalies in substituted β‐lactams

Crull,

Buevich,

Martin

et al. 2024

Magnetic Reson in Chemistry

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Abstractβ‐lactams are a chemically diverse group of molecules with a wide range of biological activities. Having recently observed curious trends in 2JHH coupling values in studies on this structural class, we sought to obtain a more comprehensive understanding of these diagnostic NMR parameters, specifically interrogating 1JCH, 2JCH, and 2JHH, to differentiate 3‐ and 4‐monosubstituted β‐lactams. Further investigation using computational chemistry methods was employed to explore the geometric and electronic origins for the observed and calculated differences between the two substitution patterns.

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β-Lactams from the Ocean

Cited by 8 publications

References 168 publications

Drug Discovery in the Field of β-Lactams: An Academic Perspective

Drug Discovery in the Field of β-Lactams: An Academic Perspective

β-Lactams and Ureas as Cross Inhibitors of Prokaryotic Systems

DFT investigation of coupling constant anomalies in substituted β‐lactams

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