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 Applications

Testing Sterility of Blood Cultures

Blood cultures are routinely prepared in order to test for bacterial infection. False negative results might be obtained where the blood sample contains antibiotics. Incorporation of β-Lactamase in the culture medium will overcome this problem when cephalosporins/penicillins are present

Testing for Contamination of Drugs by Antibiotics

US Code of Federal regulations states that “If a reasonable possibility exists that a non-penicillin drug product has been exposed to cross-contamination with penicillin, the non-penicillin drug product shall be tested for the presence of penicillin” (21 CFR 211.176, Penicillin Contamination, FDA, BY-Lines No. 8 November 1977)

Environmental monitoring

Monitoring within antibiotic manufacturing areas

Sterility Testing of Bulk Antibiotics

As described by US Pharmcopeia (USP) Chapter 71 and EP Section 2.6

Additional Reading

Download E-Brochure: Antibiotics

 

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