Structure of the extended-spectrum class C β-lactamase ADC-1 from<i>Acinetobacter baumannii</i>

Bhattacharya, Monolekha; Tóth, Márta; Antunes, Nuno T.; Smith, Clyde A.; Vakulenko, Sergei B.

doi:10.1107/s1399004713033014

Cited by 26 publications

(32 citation statements)

References 59 publications

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“…Class C extendedspectrum β-lactamase ADC-26 was seen upregulated in our study in JU0126 strain. The overexpression of ADC is reported to confer resistance to a range of β-lactam antibiotics making the infections caused by A. baumannii difficult to treat [29]. However, the overexpression in the eravacycline treated JU0126 could be due to a random antibiotic stress response because these βlactamases does not have substrate specificity for a nonβ-lactam drug.…”

Section: Upregulated Degs/proteinsmentioning

confidence: 99%

Integrative analysis of outer membrane vesicles proteomics and whole-cell transcriptome analysis of eravacycline induced Acinetobacter baumannii strains

Kesavan

Vasudevan

et al. 2020

BMC Microbiol

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Background: Acinetobacter baumannii is a multidrug-resistant (MDR) hazardous bacterium with very high antimicrobial resistance profiles. Outer membrane vesicles (OMVs) help directly and/or indirectly towards antibiotic resistance in these organisms. The present study aims to look on the proteomic profile of OMV as well as on the bacterial transcriptome upon exposure and induction with eravacycline, a new synthetic fluorocycline. RNA sequencing analysis of whole-cell and LC-MS/MS proteomic profiling of OMV proteome abundance were done to identify the differential expression among the eravacycline-induced A. baumannii ATCC 19606 and A. baumannii clinical strain JU0126. Results: The differentially expressed genes from the RNA sequencing were analysed using R package and bioinformatics software and tools. Genes encoding drug efflux and membrane transport were upregulated among the DEGs from both ATCC 19606 and JU0126 strains. As evident with the induction of eravacycline resistance, ribosomal proteins were upregulated in both the strains in the transcriptome profiles and also resistance pumps, such as MFS, RND, MATE and ABC transporters. High expression of stress and survival proteins were predominant in the OMVs proteome with ribosomal proteins, chaperons, OMPs OmpA, Omp38 upregulated in ATCC 19606 strain and ribosomal proteins, toluene tolerance protein, siderophore receptor and peptidases in the JU0126 strain. The induction of resistance to eravacycline was supported by the presence of upregulation of ribosomal proteins, resistance-conferring factors and stress proteins in both the strains of A. baumannii ATCC 19606 and JU0126, with the whole-cell gene transcriptome towards both resistance and stress genes while the OMVs proteome enriched more with survival proteins.Conclusion: The induction of resistance to eravacycline in the strains were evident with the increased expression of ribosomal and transcription related genes/proteins. Apart from this resistance-conferring efflux pumps, outer membrane proteins and stress-related proteins were also an essential part of the upregulated DEGs. However, the expression profiles of OMVs proteome in the study was independent with respect to the whole-cell RNA expression profiles with low to no correlation. This indicates the possible role of OMVs to be more of back-up additional protection to the existing bacterial cell defence during the antibacterial stress.

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Section: Upregulated Degs/proteinsmentioning

confidence: 99%

Integrative analysis of outer membrane vesicles proteomics and whole-cell transcriptome analysis of eravacycline induced Acinetobacter baumannii strains

Kesavan

Vasudevan

et al. 2020

BMC Microbiol

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“…The molecular structure of class C β-lactamases consists of two domains of different sizes. The bigger domain contains a central antiparallel beta sheet flanked by alpha helices at each side, while the smaller domain is entirely composed of alpha helices and contains the catalytic serine residue [7,[9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Molecular Characterization of a Novel Family VIII Esterase with β-Lactamase Activity (PsEstA) from Paenibacillus sp.

et al. 2019

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Molecular information about family VIII esterases, which have similarities with class C β-lactamases and penicillin-binding proteins, remains largely unknown. In this study, a novel family VIII esterase with β-lactamase activity (PsEstA) from Paenibacillus sp. was characterized using several biochemical and biophysical methods. PsEstA was effective on a broad range of substrates including tertiary butyl acetate, glyceryl tributyrate, glucose pentaacetate, olive oil, and p-nitrophenyl esters. Additionally, PsEstA hydrolyzed nitrocefin, cefotaxime, and 7-aminocephalosporanic acid. Interestingly, two forms of immobilized PsEstA (CLEAs-PsEstA and mCLEAs-PsEstA) showed high recycling property and enhanced stability, but hybrid nanoflowers (hNFs) of PsEstA require improvement. This study provides a molecular understanding of substrate specificities, catalytic regulation, and immobilization of PsEstA, which can be efficiently used in biotechnological applications.

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“…3A and supplemental Fig. S4) (37). According to the model, Ser-88 and Ser-90 are located in the catalytic motif S 88 VS 90 K 91 of typical ␤-lactamases (domain 2), whereas Ser-81 and Thr-151 are positioned relatively close to the protein surface, based on their locations in domain 1 and the P2-loop domain, respectively (Fig.…”

Section: Comparison Of a Baumannii Sk17-s And Sk17-r Phos-mentioning

confidence: 99%

“…The refined 1.2Å resolution crystal structure of ADC-1, the extended-spectrum class C ␤-lactamase Acinetobacter-derived cephalosporinase (Protein Data bank (PDB): 4net), was used to construct the active site of SK17 AmpC, based on the 99% sequence identity between these two enzymes (37). The bioinformatics tools PDB, and Discovery Studio 4.0 (Accelrys, San Diego, CA) were used to build a homology model using default protocols.…”

Section: Nanolc-ms/msmentioning

confidence: 99%

Comparative Phosphoproteomics Reveals the Role of AmpC β-lactamase Phosphorylation in the Clinical Imipenem-resistant Strain Acinetobacter baumannii SK17

Lai

Yang

Chern

et al. 2016

Molecular & Cellular Proteomics

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Nosocomial infectious outbreaks caused by multidrugresistant Acinetobacter baumannii have emerged as a serious threat to human health. Phosphoproteomics of pathogenic bacteria has been used to identify the mechanisms of bacterial virulence and antimicrobial resistance. In this study, we used a shotgun strategy combined with high-accuracy mass spectrometry to analyze the phosphoproteomics of the imipenem-susceptible strain SK17-S and -resistant strain SK17-R. We identified 410 phosphosites on 248 unique phosphoproteins in SK17-S and 285 phosphosites on 211 unique phosphoproteins in SK17-R. The distributions of the Ser/Thr/Tyr/Asp/His phosphosites in SK17-S and SK17-R were 47.0%/27.6%/ 12.4%/8.0%/4.9% versus 41.4%/29.5%/17.5%/6.7%/ 4.9%, respectively. The Ser-90 phosphosite, located on the catalytic motif S 88 VS 90 K of the AmpC ␤-lactamase, was first identified in SK17-S. Based on site-directed mutagenesis, the nonphosphorylatable mutant S90A was found to be more resistant to imipenem, whereas the phosphorylation-simulated mutant S90D was sensitive to imipenem. Additionally, the S90A mutant protein exhibited higher ␤-lactamase activity and conferred greater bacterial protection against imipenem in SK17-S compared with the wild-type. In sum, our results revealed that in A. baumannii, Ser-90 phosphorylation of AmpC negatively regulates both ␤-lactamase activity and the ability to counteract the antibiotic effects of imipenem. These findings highlight the impact of phosphorylation-mediated regulation in antibiotic-resistant bacteria on future drug design and new therapies.

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Structure of the extended-spectrum class C β-lactamase ADC-1 fromAcinetobacter baumannii

Cited by 26 publications

References 59 publications

Integrative analysis of outer membrane vesicles proteomics and whole-cell transcriptome analysis of eravacycline induced Acinetobacter baumannii strains

Integrative analysis of outer membrane vesicles proteomics and whole-cell transcriptome analysis of eravacycline induced Acinetobacter baumannii strains

Molecular Characterization of a Novel Family VIII Esterase with β-Lactamase Activity (PsEstA) from Paenibacillus sp.

Comparative Phosphoproteomics Reveals the Role of AmpC β-lactamase Phosphorylation in the Clinical Imipenem-resistant Strain Acinetobacter baumannii SK17

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