Synthesis and SAR of thioester and thiol inhibitors of IMP-1 Metallo-β-Lactamase

Greenlee, Mark L.; Laub, Joanne B.; Balkovec, James M.; Hammond, Milton L.; Hammond, Gail G.; Pompliano, David L.; Epstein-Toney, Jeffrey H.

doi:10.1016/s0960-894x(99)00425-4

Cited by 63 publications

(39 citation statements)

References 29 publications

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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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Section: Experimental Inhibitors Of Mblsmentioning

confidence: 99%

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

et al. 2005

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“…Because of the great interest in MBL inhibition, several classes of inhibitors have been described (17,18); these include phenazines (19), ketone derivatives of L-and D-alanine and trifluoromethyl alcohol (20), thioesters (21,22), biphenyl tetrazoles (23,24), amino acid-derived hydroxamates (25), thiols (26 -30), and tricyclic natural products (31). However, despite many of these having good inhibitory properties, only a few thiols have a broad spectrum of inhibition for MBLs.…”

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confidence: 99%

The 1.5-Å Structure of Chryseobacterium meningosepticum Zinc β-Lactamase in Complex with the Inhibitor, D-Captopril

Garcia-Saez

Hopkins

Papamicaël³

et al. 2003

Journal of Biological Chemistry

130

124

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The crystal structure of the class-B ␤-lactamase, BlaB, from the pathogenic bacterium, Chryseobacterium meningosepticum, in complex with the inhibitor, D-captopril, has been solved at 1.5-Å resolution. The enzyme has the typical ␣␤/␤␣ metallo-␤-lactamase fold and the characteristic two metal binding sites of members of the subclass B1, in which two Zn 2؉ ions were identified. D-Captopril, a diastereoisomer of the commercial drug, captopril, acts as an inhibitor by displacing the catalytic hydroxyl ion required for antibiotic hydrolysis and intercalating its sulfhydryl group between the two Zn 2؉ ions. Interestingly, D-captopril is located on one side of the active site cleft. The x-ray structure of the complex of the closely related enzyme, IMP-1, with a mercaptocarboxylate inhibitor, which also contains a sulfhydryl group bound to the two Zn 2؉ ions, shows the ligand to be located on the opposite side of the active site cleft. A molecule generated by fusion of these two inhibitors would cover the entire cleft, suggesting an interesting approach to the design of highly specific inhibitors.

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“…Some of the reported inhibitors of these enzymes include trifluoromethyl alcohols and ketones (41), amino acid-derived hydroxamates (42), thiols (3,4,12,13), thioester derivatives (13,14,31,32), cysteinyl peptides (5), biphenyl tetrazoles (38,39), mercaptocarboxylates (24,30), 1␤-methylcarbapenem derivatives (25,26), a synthetic cephamycin (34), and 2,3-disubstituted succinic acid derivatives (40).…”

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confidence: 99%

N-Arylsulfonyl Hydrazones as Inhibitors of IMP-1 Metallo-β-Lactamase

Siemann

Evanoff

Marrone

et al. 2002

Antimicrob Agents Chemother

108

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Members of a family of N-arylsulfonyl hydrazones have been identified as novel inhibitors of IMP-1, a metallo-␤-lactamase of increasing prevalence. Structure-activity relationship studies have indicated a requirement for bulky aromatic substituents on each side of the sulfonyl hydrazone backbone for these compounds to serve as efficient inhibitors of IMP-1. Molecular modeling has provided insight into the structural basis for the anti-metallo-␤-lactamase activity exhibited by this class of compounds.

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Synthesis and SAR of thioester and thiol inhibitors of IMP-1 Metallo-β-Lactamase

Cited by 63 publications

References 29 publications

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

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

The 1.5-Å Structure of Chryseobacterium meningosepticum Zinc β-Lactamase in Complex with the Inhibitor, D-Captopril

N-Arylsulfonyl Hydrazones as Inhibitors of IMP-1 Metallo-β-Lactamase

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