Beta Lactamase Inhibitor

A beta-lactamase is a family of enzyme that is resistance to beta-lactam antibiotics. They are produced by bacteria that have multiple resistance to β-lactam antibiotics. Examples of beta lactamase antibiotics are penicillins, carbapenems, cephalosporins, and cephamycins.

What the enzymes do is they open the beta-lactam ring and inactive the healing effect of the antibiotics. The bacteria that produce beta-lactamase play a vital role in polymicrobial infection. They can directly cause an infection or could develop a secondary infection due to their ability to produce beta lactamase enzyme.

Penicillin therapy won’t work because beta-lactamase can survive even with penicillin. As a matter of fact, they can protect other penicillin susceptible organisms by simply releasing free enzymes into the environment. This phenomenon occurs in infections involving the skin, respiratory track, and soft tissues. ^{(1, 2)}

Beta lactamase hydrolyzes the beta-lactam ring, which is the building block of beta-lactam antibiotics. The first beta-lactam antibiotic was penicillin. However, there are reported cases of beta-lactam antibiotic resistant bacterial strains. The production of beta-lactamase greatly affects the potency of the antibiotic.

For the beta-lactam antibiotics to deliver its therapeutic effects, the release of beta-lactamase should be stopped. This has paved way to the development of beta-lactamase inhibitors. This type of drugs prevents the release of beta-lactamase enzyme.

In case of release, the beta-lactamase inhibitor will be the one to catch the enzymes so that the beta-lactam antibiotic will be able to perform its functions. ^{(1, 2, 3)}

Image 1 : A molecular presentation of beta-lactamase inhibitor drugs, how they function, and how they inhibit the release of beta-lactamase enzymes.
Picture Source : www.pnas.org

 

Figure 2 : An image showing the functions of beta-lactamase inhibitor in fighting disease causing microorganisms.
Photo Source : image.slidesharecdn.com

Photo 3 : beta-lactam antibiotic that is made even more strong and effective by adding beta-lactamase inhibitor.
Image Source : slideplayer.com

Beta lactamase classification

1. Molecular classification – It is based on the amino acid sequence, which divides beta lactamase into class A, B, C, and D. Class A, C, and D use serine for the hydrolysis of β-lactam. On the other hand, substrate hydrolysis of class B requires divalent zinc ions. (4)
2. Functional classification – It groups the enzymes based on the substrate and inhibitor profiles.

• Group 1 – It includes the class C, which are cephalosporinases. They are present on many Enterobacteriaceae and other organisms.
• Group 2 – Incudes classes A and D, they are broad-spectrum, inhibitor-resistant. This is the largest group of β-lactamases. ^{(4, 5)}
• Group 3 Metallo-β-lactamases (MBLs) – They are a distinct group of beta-lactamase. They were identified as chromosomal enzymes commonly found in Gram-positive or occasional Gram-negative bacilli like Stenotrophomonas maltophilia. ⁽⁵⁾

What are Beta-lactamase inhibitors?

Beta-lactamase inhibitors are drugs that block or hinder the activity of beta-lactamase enzymes. They are used in combination with beta-lactam antibiotics because of their ability to enhance the therapeutic effect of the drugs.

Using beta-lactamase inhibitor will result in successfully blocking the enzymes produced by gram positive bacteria such as Staph aureus and a few gram negative bacteria like H. influenzae, Moraxella catarrhalis, and Neisseria gonorrhoeae.

It is important to block the action of beta-lactamase enzymes. Failure to do so could lead to antibiotic resistance. ^{(5, 6,7)}

There are two primary beta lactamase inhibitors classification. They are:

• Β lactamase inhibitor with beta lactam core
• Β lactamase inhibitor without beta lactam group

Beta lactamase inhibitor Mechanism of Action (MOA)

There are different species of bacteria. Some bacteria are resistant to beta-lactam antibiotics. They develop resistance by producing B-lactamases enzyme. Beta-lactam antibiotics contain a ring in their molecular structure. Examples of B-lactam drugs are penicillins, cephalosphorins, cephamycins, and monolactams.

It works by binding to the penicillin binding protein. The binding process makes it difficult for the penicillin binding protein to crosslink peptidoglycan chains. As a result, it would be extremely difficult for the bacteria to synthesize a stable cell wall. Through this process, the disease causing bacteria is lysed. ^{(7, 8,9)}

However, there are instances when beta-lactam is not strong enough to kill the disease causing bacteria. This is true in the specie of Methicillin-resistant Staphylococcus aureus (MRSA) bacteria. They are resistant to Beta-lactam as they have the ability to produce beta-lactamases enzyme. These enzymes deactivates the effect of antibiotic by breaking the ring. As a result, the microorganism develops resistance to antibiotic.

To overcome the resistance, beta-lactamase inhibitor should be used. The beta-lactam and beta-lactamase inhibitor should be used together to achieve a synergistic effect. An example of beta-lactamase inhibitor is clavulanic acid. It acts as a suicide molecule.

It binds to the B-lactamases enzyme and deactivates it. A beta-lactam will then be used to attack the bacteria, targeting those bacteria that are not yet resistant to antibiotics. Beta-lactam and beta-lactamase inhibitor work hand in hand to successfully get rid of the disease causing microorganisms. It is the primary reason why doctors prescribe these drugs. ^{(5, 6, 8,9)}

Beta-lactam and Beta-lactamase inhibitor drugs combinations

• Amoxicillin-clavulanate – This drug combination prevents the strain of oxacillin-sensitive Staphylococcus aureus and beta-lactamase producing Haemophilus influenza. It is extremely helpful in patients with sinusitis, otitis media, bite wounds, lower respiratory infection, and urinary tract infection.
• Ampicillin-sulbactam – This drug combination is used as prophylaxis and drug therapy for pelvic infections and intra-abdominal infections. ^{(8, 9)}

Examples of beta-lactamase inhibitors

• Avibactam combined with ceftazidimine
• Sulbactam combined with unasyn/ampicillin
• Clavulanic acid combined with amoxicillin ⁽¹⁰⁾

What is beta-lactamase inhibitor protein (BLIP)?

This type of beta-lactamase inhibitor protein is produced by the species of Streptomyces. It plays an essential role in preventing the action of beta-lactamase like TEM-1. The TEM-1 has a strong resistance to penicillin antibiotics. What the beta-lactamase inhibitor protein does is it binds to TEM-1 and directly gets in contact with the active site residues of TEM-1.

Aside from preventing the action of TEM-1, beta-lactamase inhibitor protein can also prevent action of other classes of beta-lactamases. It is the primary reason why beta-lactamase inhibitor protein is one of the widely used drugs in treating B-lactam resistant microorganisms. ^{(7, 8, 11)}

References:

1. www.drugs.com
2. https://en.wikipedia.org/
3. www.ncbi.nlm.nih.gov
4. www.uptodate.com
5. www.goodrx.com
6. www.venatorx.com
7. www.pharmaceutical-journal.com
8. www.aafp.org
9. www.sciencedirect.com
10. www.themedicinescompany.com
11. accesspharmacy.mhmedical.com