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ACS Chem Neurosci. 2017 Oct 18;8(10):2132-2138. doi: 10.1021/acschemneuro.7b00232. Epub 2017 Aug 14.

Metallo-β-lactamase Domain-Containing Protein 1 (MBLAC1) Is a Specific, High-Affinity Target for the Glutamate Transporter Inducer Ceftriaxone.

Author information

1
Department of Biomedical Science and Brain Institute, Charles E. Schmidt College of Medicine, Florida Atlantic University , Jupiter, Florida 33458, United States.

Abstract

Ceftriaxone, a β-lactam antibiotic, has been reported to act independently of its antimicrobial actions to normalize perturbed central nervous system glutamate levels, principally by elevating expression of glial glutamate transporters. Identification of a specific, high-affinity target for ceftriaxone could significantly impact therapeutic development for multiple brain disorders, ranging from neurodegenerative disorders to addiction. Recently, we identified a glial-expressed Caenorhabditis elegans gene, swip-10, that encodes a metallo-β-lactamase domain-containing protein, and limits glutamate-dependent changes in dopamine neuron excitability. Bioinformatic analyses identified MBLAC1 as the likely mammalian orthologue of swip-10. Using cyanogen bromide immobilized ceftriaxone for affinity capture experiments and backscattering interferometry to monitor MBLAC1 binding of unmodified ceftriaxone, we obtained evidence for specific, high affinity (KD = 2.2 μM) binding of ceftriaxone to MBLAC1. We discuss our findings with respect to MBLAC1 as a potentially exclusive, high-affinity binding partner of ceftriaxone in the CNS, and the path forward in the development of novel, MBLAC1-based therapeutics.

KEYWORDS:

Ceftriaxone; MBLAC1; antibiotic; metallo-β-lactamase

PMID:
28783953
DOI:
10.1021/acschemneuro.7b00232
[Indexed for MEDLINE]

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