Beta-lactam antibiotics contain a cyclic amide ring of which mimics the structure of the terminal amino acid residues comprising the peptidoglycan matrix. It is this structure that the enzyme beta lactamase acts upon as a method of antibiotic defense, hydrolyzing the ring and compromising the structure as a result. Structure and function are intrinsically related; without proper structure, the function is altered and lost in most cases altogether. Inhibiting the function of the beta-lactamase enzyme are substances such as clavulanic acid that contain the beta-lactam ring as well. The analogous structure is the basis of studying the possible anti-seizure effects beta lactamase inhibitors possess.
Glutamate and Ceftriaxone
Ceftriaxone, a beta-lactam antibiotic, displays anti-glutamate effects. Glutamate plays a role in the onset of epilepsy, activating ligand-gated ion channels and results in the increase of sodium and calcium. Ceftriaxone has been shown to modulate the glutamate transporter in a manner that offers protection from seizures via enhancing glutamate uptake. The particular glutamate transporter, glutamate transporter subtype 1 (GLT-1), has been recognized as a subject for CNS research targeted towards managing excessive glutamate transmission and the complications that follow. Despite ceftriaxone exhibiting beneficial effects in terms of anti-seizure activity, the poor brain permeability of ceftriaxone forces a high dosage requirement for anti-seizure effects to take place in potential clinical trials. The potential of beta-lactamase inhibitors of which are structurally similar to that of ceftriaxone, therefore, became a target of interest for anti-seizure CNS-focused research.
Exploring Beta Lactamase Inhibitors in CNS Research
Rawls et al. conducted a study to observe the effects of beta-lactamase inhibitors containing the same beta-lactam ring structure, such as clavulanic acid and tazobactam, and their effects on glutamate- and cocaine-induced seizure-like activity in an invertebrate assay. The activities of tazobactam, clavulanic acid, ceftriaxone, and vancomyocin (a non-beta lactam antibiotic utilized as a control) were observed and compared in an invertebrate assay of which screened anti-seizure activities. The seizure-like activities were quantified as the number of C-like hyperkinesias occurring during glutamate and cocaine exposure. Clavulanic acid weakened the effects of glutamate-induced seizure-like activity. The effect of clavulanic acid on seizure-like activity was more robust in cocaine-induced seizure-like activity at lower concentrations, displaying inhibitory effects for both types of seizure-like activities. Similarly, tazobactam significantly inhibited seizure-like activity induced by both substances. Vancomyocin did not affect induced seizure-like activity at a significant level.
In addition to the substances listed above, dihydrokainate was also observed at differing concentrations for its effects upon induced seizure-like activities in the invertebrate assay. At lower concentrations, dihydrokainate displayed inhibitory effects upon glutamate- and cocaine-induced seizure-like activity; however, higher concentrations of dihydrokainate actually induced seizure-like activity in the planarian assay. The effects of dihydrokainate in the assay raise the possibility of blocking glutamate uptake augmenting seizure-like activity.
Beta-lactamase inhibitors displayed the ability to inhibit seizure-like activities, much like the beta-lactam antibiotic ceftriaxone. The lack of inhibition with the non-beta lactam antibiotic vancomyocin implies that the presence of the beta-lactam ring, not the antibacterial activity, is the key component in seizure inhibition. Additionally, both beta-lactamase inhibitors present in the study differ from ceftriaxone in that they lack the primary amine present in ceftriaxone. Anti-glutamate properties via the GLT-1 transporter, however, cannot be determined from this study. Further experimentation on other animal models can reveal more about beta-lactamase inhibitors and their anti-seizure roles.
Beta-lactamase is especially effective in body fluids and thus have 2 main applications in clinical laboratory settings. Diagnosing bacterial infections by preparing a blood culture and in Aminoglycoside Antibiotic Assays.
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Rawls SM, Karaca F, Madhani I, et al. beta-lactamase inhibitors display anti-seizure properties in an invertebrate assay. Neuroscience. 2010;169(4):1800-1804. doi:10.1016/j.neuroscience.2010.06.041.