The sequence-activity relationship between metallo-β-lactamases IMP-1, IMP-6, and IMP-25 suggests an evolutionary adaptation to meropenem exposure.


Abstract

Metallo-β-lactamases are important determinants of antibacterial resistance. In this study, we investigate the sequence-activity relationship between the closely related enzymes IMP-1, IMP-6, and IMP-25. While IMP-1 is the more efficient enzyme across the overall spectrum of tested β-lactam antibacterial agents, IMP-6 and IMP-25 seem to have evolved to specifically inactivate the newer carbapenem meropenem. Molecular modeling indicates that the G235S mutation distinguishing IMP-25 from IMP-1 and IMP-6 may affect enzyme activity via Asn233.

Submission Details

ID: mpDnA5cC

Submitter: Peter Oelschlaeger

Submission Date: Jan. 11, 2019, 4:04 p.m.

Version: 1

Publication Details
Liu EM;Pegg KM;Oelschlaeger P,Antimicrob Agents Chemother (2012) The sequence-activity relationship between metallo-β-lactamases IMP-1, IMP-6, and IMP-25 suggests an evolutionary adaptation to meropenem exposure. PMID:23006757
Additional Information

Corrections: (1) kcat for IMP-25 (mutant G169S+S196G) with cefoxotin was misreported as 30 1/s in the original publication. It should be 90 1/s. (2) kcat for IMP-25 (mutant G169S+S196G) with ampicillin was misreported as 67 1/s. It should be 47 1/s. Explanation of amino acid numbering: (1) Mutant S196G is actually a wild-type enzyme called IMP-6. According to the standard numbering scheme (PMID 15215079) , its mutation is S262G. (2) Mutant G169S+S196G is actually a wild-type enzyme called IMP-25. According to the standard numbering scheme, its mutations are G235S and S262G. Abbreviations: (1) ND indicates not detectable (used for kinetic constants with aztreonam).

Structure view and single mutant data analysis

Study data

No weblogo for data of varying length.
Colors: D E R H K S T N Q A V I L M F Y W C G P
 

Data Distribution

Studies with similar sequences (approximate matches)

Correlation with other assays (exact sequence matches)


Relevant PDB Entries

Structure ID Release Date Resolution Structure Title
6JED 2019-08-07 1.57 Crystal structure of IMP-1 metallo-beta-lactamase in a complex with MCR
5Y5B 2018-08-08 1.7 Crystal Structure Of IMP-1 Metallo-beta-lactamase
4C1G 2014-08-27 1.71 Crystal structure of the metallo-beta-lactamase IMP-1 with D-captopril
5EV6 2016-06-01 1.98 Crystal structure of the native, di-zinc metallo-beta-lactamase IMP-1
1DD6 2000-11-08 2.0 IMP-1 METALLO BETA-LACTAMASE FROM PSEUDOMONAS AERUGINOSA IN COMPLEX WITH A MERCAPTOCARBOXYLATE INHIBITOR
5HH4 2017-01-18 2.0 Crystal structure of metallo-beta-lactamase IMP-1 in complex with a phosphonate-based inhibitor
4C1F 2014-08-27 2.01 Crystal structure of the metallo-beta-lactamase IMP-1 with L-captopril
1WUO 2005-03-29 2.01 Crystal structure of metallo-beta-lactamase IMP-1 mutant (D81A)
5EV8 2016-06-01 2.3 Crystal structure of the metallo-beta-lactamase IMP-1 in complex with the bisthiazolidine inhibitor D-CS319
5EWA 2016-06-01 2.3 Crystal structure of the metallo-beta-lactamase IMP-1 in complex with the bisthiazolidine inhibitor L-VC26
1VGN 2005-06-21 2.63 Structure-based design of the irreversible inhibitors to metallo--lactamase (IMP-1)
1WUP 2005-03-29 3.0 Crystal structure of metallo-beta-lactamase IMP-1 mutant (D81E)

Relevant UniProtKB Entries

Percent Identity Matching Chains Protein Accession Entry Name
100.0 Metallo-beta-lactamase type 2 P52699 BLAB_SERMA