The biogenesis of β-lactamase enzymes

Kaderabkova, Nikol; Bharathwaj, Manasa; Furniss, R. Christopher D.; González, Diego; Palmer, Tracy; Mavridou, Despoina A. I.

doi:10.1099/mic.0.001217

Cited by 8 publications

(5 citation statements)

References 309 publications

(588 reference statements)

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“…Since Fdx is generally not active against Gram-negative bacteria, [11] we wondered if this lack of activity is caused by insufficient RNAP inhibition, impaired cell permeation, or efflux. [42,43] In addition, Fdx-dependent inhibition of Gram-negative RNAP is generally weaker than that of C. difficile RNAP. The "Fdx sensitizer position" Lys84 of C. difficile is exchanged for neutral or negatively charged residues in Gramnegative bacteria, greatly reducing activity.…”

Section: Resultsmentioning

confidence: 99%

Phenolic Substitution in Fidaxomicin: A Semisynthetic Approach to Antibiotic Activity Across Species**

Jung,

Kraimps,

Dittmann

et al. 2023

ChemBioChem

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Fidaxomicin (Fdx) is a natural product antibiotic with potent activity against Clostridioides difficile and other Gram‐positive bacteria such as Mycobacterium tuberculosis. Only few Fdx derivatives have been synthesized and examined for their biological activity in the 50 years since its discovery. Fdx has a well‐studied mechanism of action, namely inhibition of the bacterial RNA polymerase. Yet, the targeted organisms harbor different target protein sequences, which poses a challenge for the rational development of new semisynthetic Fdx derivatives. We introduced substituents on the two phenolic hydroxy groups of Fdx and evaluated the resulting trends in antibiotic activity against M. tuberculosis, C. difficile, and the Gram‐negative model organism Caulobacter crescentus. As suggested by the target protein structures, we identified the preferable derivatisation site for each organism. The derivative ortho‐methyl Fdx also exhibited activity against the Gram‐negative C. crescentus wild type, a first for fidaxomicin antibiotics. These insights will guide the synthesis of next‐generation fidaxomicin antibiotics.

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Section: Resultsmentioning

confidence: 99%

Phenolic Substitution in Fidaxomicin: A Semisynthetic Approach to Antibiotic Activity Across Species**

Jung,

Kraimps,

Dittmann

et al. 2023

ChemBioChem

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“…The translation of the nucleotide indicates an open reading frame (ORF) of 333 amino acids. As ABLs are synthesized as a precursor in the cytoplasm and then secreted into the periplasm (Kaderabkova et al, 2022), we explored the possibility of the presence of a peptide signal. We analyzed the sequence with the SignalP server (Teufel et al, 2022), which enabled us to identify a probable secretion signal with a cleavage site between Ala53 and Cys54.…”

Section: Gene Amplification Construct Design and Protein Expressionmentioning

confidence: 99%

Biochemical and structural characterization of a class A β-lactamase from Nocardia cyriacigeorgica

Feuillard,

Couston,

Benito

et al. 2024

Acta Cryst Sect F

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Nocardia are Gram-positive bacteria from the Actinobacteria phylum. Some Nocardia species can infect humans and are usually considered to be opportunist pathogens, as they often infect immunocompromised patients. Although their clinical incidence is low, many Nocardia species are now considered to be emerging pathogens. Primary sites of infection by Nocardia are the skin or the lungs, but dissemination to other body parts is very frequent. These disseminated infections are very difficult to treat and thus are tackled with multiple classes of antibiotics, in addition to the traditional treatment targeting the folate pathway. β-Lactams are often included in the regimen, but many Nocardia species present moderate or strong resistance to some members of this drug class. Genomic, microbiological and biochemical studies have reported the presence of class A β-lactamases (ABLs) in a handful of Nocardia species, but no structural investigation of Nocardia β-lactamases has yet been performed. In this study, the expression, purification and preliminary biochemical characterization of an ABL from an N. cyriacigeorgica (NCY-1) clinical strain are reported. The crystallization and the very high resolution crystal structure of NCY-1 are also described. The sequence and structural analysis of the protein demonstrate that NCY-1 belongs to the class A1 β-lactamases and show its very high conservation with ABLs from other human-pathogenic Nocardia. In addition, the presence of one molecule of citrate tightly bound in the catalytic site of the enzyme is described. This structure may provide a solid basis for future drug development to specifically target Nocardia spp. β-lactamases.

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“…The insertion of class 1 integrons into Tn 402 ‐like transposons enables the Tn 402 ‐class1 integrons to transpose different replicons, including conjugative plasmids and spread rapidly. INTEGRALL contains several class 1 integrons with relatively new ARGs, including genes encoding carbapenemases, bla VIM , bla GES and bla IMP (Kaderabkova et al., 2022 ). IntegronFinder is a highly accurate tool for detecting integrons in DNA sequences using HMM profiles for essential protein detection and covariance models for recombination site detection, while also offering the ability to annotate gene cassettes (Cury et al., 2016 ; Néron et al., 2022 ).…”

Section: General Features Of Representative Mgesmentioning

confidence: 99%

Microbial evolution through horizontal gene transfer by mobile genetic elements

Tokuda,

Shintani

2024

Microbial Biotechnology

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Mobile genetic elements (MGEs) are crucial for horizontal gene transfer (HGT) in bacteria and facilitate their rapid evolution and adaptation. MGEs include plasmids, integrative and conjugative elements, transposons, insertion sequences and bacteriophages. Notably, the spread of antimicrobial resistance genes (ARGs), which poses a serious threat to public health, is primarily attributable to HGT through MGEs. This mini‐review aims to provide an overview of the mechanisms by which MGEs mediate HGT in microbes. Specifically, the behaviour of conjugative plasmids in different environments and conditions was discussed, and recent methodologies for tracing the dynamics of MGEs were summarised. A comprehensive understanding of the mechanisms underlying HGT and the role of MGEs in bacterial evolution and adaptation is important to develop strategies to combat the spread of ARGs.

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The biogenesis of β-lactamase enzymes

Cited by 8 publications

References 309 publications

Phenolic Substitution in Fidaxomicin: A Semisynthetic Approach to Antibiotic Activity Across Species**

Phenolic Substitution in Fidaxomicin: A Semisynthetic Approach to Antibiotic Activity Across Species**

Biochemical and structural characterization of a class A β-lactamase from Nocardia cyriacigeorgica

Microbial evolution through horizontal gene transfer by mobile genetic elements

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