Inhibition of the Metallo-.BETA.-lactamase Produced from Serratia marcescens by Thiol Compounds.

Goto, Masafumi; Takahashi, Tatsuya; Yamashita, Fumiko; Koreeda, Ako; Mori, Hidefumi; Ohta, Michio; Arakawa, Yoshichika

doi:10.1248/bpb.20.1136

Cited by 64 publications

(54 citation statements)

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“…MCR is known as a reversible competitive inhibitor against the IMP-1 MBL, which belongs to subclass B1 (46). We determined the K i value of SMB-1 for MCR to be 9.4 Ϯ 0.4 M, suggesting that MCR could behave as a potent inhibitor for SMB-1.…”

Section: Resultsmentioning

confidence: 88%

Structural Insights into the Subclass B3 Metallo-β-Lactamase SMB-1 and the Mode of Inhibition by the Common Metallo-β-Lactamase Inhibitor Mercaptoacetate

Wachino

Yamaguchi

Mori

et al. 2013

Antimicrob Agents Chemother

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A novel subclass B3 metallo-␤-lactamase (MBL), SMB-1, recently identified from a Serratia marcescens clinical isolate, showed a higher hydrolytic activity against a wide range of ␤-lactams than did the other subclass B3 MBLs, i.e., BJP-1 and FEZ-1, from environmental bacteria. To identify the mechanism underlying the differences in substrate specificity among the subclass B3 MBLs, we determined the structure of SMB-1, using 1.6-Å diffraction data. Consequently, we found that SMB-1 reserves a space in the active site to accommodate ␤-lactam, even with a bulky R1 side chain, due to a loss of amino acid residues corresponding to F31 and L226 of BJP-1, which protrude into the active site to prevent ␤-lactam from binding. The protein also possesses a unique amino acid residue, Q157, which probably plays a role in recognition of ␤-lactams via the hydrogen bond interaction, which is missing in BJP-1 and FEZ-1, whose K m values for ␤-lactams are particularly high. In addition, we determined the mercaptoacetate (MCR)-complexed SMB-1 structure and revealed the mode of its inhibition by MCR: the thiolate group bridges to two zinc ions (Zn1 and Zn2). One of the carboxylate oxygen atoms of MCR makes contact with Zn2 and Ser221, and the other makes contact with T223 and a water molecule. Our results demonstrate the possibility that MCR could be a potent inhibitor for subclass B3 MBLs and that the screening technique using MCR as an inhibitor would be effective for detecting subclass B3 MBL producers.

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Section: Resultsmentioning

confidence: 88%

Structural Insights into the Subclass B3 Metallo-β-Lactamase SMB-1 and the Mode of Inhibition by the Common Metallo-β-Lactamase Inhibitor Mercaptoacetate

Wachino

Yamaguchi

Mori

et al. 2013

Antimicrob Agents Chemother

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“…A variety of structurally disparate compounds have been examined as MBL inhibitors, including thioester derivatives (44,58,118,119,121), trifluoromethyl alcohols and ketones (182), thiols (6,18,44,56,57,71,76,101,155,159), sulfonyl hydrazones (160), tricyclic natural products (122), succinic acid derivatives (171), biphenyl tetrazoles (169,170), cysteinyl peptides (17), mercaptocarboxylates (57, 121), 1-␤-methylcarbapenem (104, 105) cefotetan (140), thioxocephalosporins (173), and penicillin derivatives (25). The activities of these compounds against selected MBLs are summarized in Table 5.…”

Section: Experimental Inhibitors Of Mblsmentioning

confidence: 99%

Metallo-β-Lactamases: the Quiet before the Storm?

et al. 2005

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SUMMARY The ascendancy of metallo-β-lactamases within the clinical sector, while not ubiquitous, has nonetheless been dramatic; some reports indicate that nearly 30% of imipenem-resistant Pseudomonas aeruginosa strains possess a metallo-β-lactamase. Acquisition of a metallo-β-lactamase gene will invariably mediate broad-spectrum β-lactam resistance in P. aeruginosa, but the level of in vitro resistance in Acinetobacter spp. and Enterobacteriaceae is less dependable. Their clinical significance is further embellished by their ability to hydrolyze all β-lactams and by the fact that there is currently no clinical inhibitor, nor is there likely to be for the foreseeable future. The genes encoding metallo-β-lactamases are often procured by class 1 (sometimes class 3) integrons, which, in turn, are embedded in transposons, resulting in a highly transmissible genetic apparatus. Moreover, other gene cassettes within the integrons often confer resistance to aminoglycosides, precluding their use as an alternative treatment. Thus far, the metallo-β-lactamases encoded on transferable genes include IMP, VIM, SPM, and GIM and have been reported from 28 countries. Their rapid dissemination is worrisome and necessitates the implementation of not just surveillance studies but also metallo-β-lactamase inhibitor studies securing the longevity of important anti-infectives.

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“…In one bacterium, Variovarax paradoxus, 3-MPA utilization was shown to involve dioxygenation of 3-MPA to 3-sulfinopropionic acid (3-SPA), catalyzed by a CDO homologue, 3-mercaptopropionate dioxygenase (3MDO), which showed high specificity for 3-MPA but not for cysteine (6). Interestingly, 3-MPA acts as an inhibitor of metallo-␤-lactamase, an enzyme involved in antibiotic resistance in bacteria (34,35). In mammals, 3-MPA is toxic by inhibiting the oxidation of fatty acid (36,37) and the synthesis of the inhibitory neurotransmitter ␥-aminobutyric acid, resulting in deformation, seizures, or death of rats (38 -40).…”

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confidence: 99%

The Cysteine Dioxygenase Homologue from Pseudomonas aeruginosa Is a 3-Mercaptopropionate Dioxygenase

Tchesnokov

Fellner

Siakkou

et al. 2015

Journal of Biological Chemistry

117

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Background: Thiol dioxygenation is catalyzed by enzymes specific for each substrate. Results: Kinetic, structural, and spectroscopic data describe an enzyme from P. aeruginosa that is a 3-mercaptopropionate dioxygenase with secondary cysteine dioxygenase activity. Conclusion: An arginine to glutamine switch and the absence of a cis-peptide bond correlate with substrate preference. Significance: Characterization of this enzyme deepens our understanding of substrate specificity in thiol dioxygenases.

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Inhibition of the Metallo-.BETA.-lactamase Produced from Serratia marcescens by Thiol Compounds.

Cited by 64 publications

References 1 publication

Structural Insights into the Subclass B3 Metallo-β-Lactamase SMB-1 and the Mode of Inhibition by the Common Metallo-β-Lactamase Inhibitor Mercaptoacetate

Structural Insights into the Subclass B3 Metallo-β-Lactamase SMB-1 and the Mode of Inhibition by the Common Metallo-β-Lactamase Inhibitor Mercaptoacetate

Metallo-β-Lactamases: the Quiet before the Storm?

The Cysteine Dioxygenase Homologue from Pseudomonas aeruginosa Is a 3-Mercaptopropionate Dioxygenase

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