Beta lactams antibiotics: The greatest discovery, the biggest danger

Beta lactams antibiotics: The greatest discovery, the biggest danger

1. History of Beta-lactams antibiotics

The first discovered antibiotic is penicillin, which is one of the three greatest drugs in the history of medicines.
Penicillin was first isolated by the Scottish Scientist Alexander Fleming from samples of mold (Penicillium notatum) that contaminated a culture dish of Staphylococcus, producing a clear ring (lack of bacterial growth) around the mold. He subsequently purified the active ingredient from "mold juice", and found that it could kill a wide range of harmful bacterial, including streptococcus, meningococcus and the diphtheria bacillus. However, Fleming did not extend his work to clinical study because he was not able to purify enough penicillin for the experiments. The use of penicillin as a therapeutic agent to treat infections did not happen until the 1940s when Howard Walter Florey and Ernst Chain developed the biochemical methodologies.
With the diverse chemical structure of beta-lactams molecules and their respective antibacterial potency, semi-synthetic beta-lactam compounds have been developed continuously and systematically. Several decades later, though the generation of semi-synthetic compounds presented a great opportunity, natural sources continued to be explored. In 1945, Italian scientist Giuseppe Brotzu noticed the fungus Cephalosporium acremonium from the sewage outlet along the Sardinian coast. Then England scientist Abraham and Newton isolated cephalosporin C from a strain of Cephalosporium acremonium, this compound generated an entirely new family of beta-lactam antibiotics because instead of 6-APA, it possesses a nucleus of 7-ACA.

2. Structure and classification of beta-lactam antibiotics

All beta-lactam antibiotics contain the same core 4-member "beta-lactam" ring (red). This ring mimics the shape of the terminal D-Ala-D-Ala peptide sequence that serves as the substrate for cell wall transpeptidases that form covalent bonds between different peptidoglycan chains during periods of cell growth. The 4 ring structure and associated side groups result in tight binding to the active site of transpeptidases (also known as Penicillin Binding Proteins). Tight binding inhibits enzyme activity, and consequent cell wall formation.
At present, there are four major beta-lactam subgroups, and their representative drugs are shown in table below.

3. Antimicrobial activity and mechanisms of bacterial resistance

3.1 Beta-Lactams Mechanism of Action

The 4-member ring of beta-lactam antibiotics gives these compounds a three-dimensional shape that mimics the D-Ala-D-Ala peptide terminus that serves as the natural substrate for transpeptidase activity during cell wall synthesis. Tight binding of these drugs to the transpeptidase active site inhibits cell wall synthesis, resulting in a weakened cell wall that is susceptible to lysis during periods of cell growth. One of the major driving forces of cell lysis is the very high internal osmotic pressure present in bacteria, which is caused by the presence of a high concentration of proteins and other molecules that growing bacteria need to survive.

3.2 Mechanisms of Bacterial Resistance to Beta-Lactams

a) Permeability barrier: In gram-positive organisms, capsular materials may hinder access to the cytoplasmic membrane, but this rarely limits the diffusion of the cell wall inhibitors. Gram-negative bacteria have a restricting sieving mechanism (porins) in their outer membranes (external cell wall), which reduces the penetration of several types of antibiotics. Different species of gram-negative bacteria exhibit varying permeability barriers to beta-lactam antibiotics, and these impair access of the antibiotics to the membrane-associated binding proteins.

b) Beta-lactamase resistance: The important mechanism of bacterial resistance to beta-lactam antibiotics is enzymatic inactivation by beta-lactamases by cleavage of the 4-member beta-lactam ring. Cleavage results in the inability of the drugs to bind to the target PBPs. There currently are >800 different beta-lactamases, representing six major classes, with the enzyme varying with the organism and drugs targeted varying with the enzyme. The increase in the number of enzymes reflects, in part, pressure brought with the increasingly widespread use of beta-lactams and the continued manipulation of the drugs in an attempt to circumvent bacterial beta-lactamase production.

c) Specific bacterial-binding proteins: Resistance to beta-lactam antimicrobial agents can be acquired by alterations in the PBP targets of these drugs. A loss or decrease in affinity of crucial PBP can lead to a significant increase in resistance to beta-lactams.

d) Cell wall-deficient microbes: Organisms that have no cell wall, such as Mycoplasma, are intrinsically resistant to beta-lactams. A phenotypic form of resistance can occur when spheroplasts (incomplete cell wall) or protoplasts (absence of cell wall) are present. These so-called "L-forms" must be present in a hyperosmotic environment (eg, the renal medulla) to survive; otherwise, they will lyse. The clinical significance of this form of resistance is unclear.

4. Common detection methods

i) Microbiological assay
[Principle]:
Antimicrobial residues in milk were determined qualitatively or quantitatively according to the inhibition of antibiotics on the physiological function and metabolism of microorganisms.
[Advantages and disadvantages]:
Low cost, long detection time, color change is not easy to observe.
[Scope of application]:
Conventional laboratory.

ii) Physicochemical analysis
[Principle]:
The specific reaction or properties of groups in antibiotic molecules are used to determine their content
[Advantages and disadvantages]:
Fast speed, high efficiency, stable result, good repeatability, reliable accuracy, automated operation. In other hand, the experimental condition request is high, needs to equip the specialized test operator, and the reagent cost, instrument and test expense is high.
[Scope of application]:
This method is not suitable for a large number of sample screening, can only be applied to accurately quantitative sample detection.

iii) Immunological analysis
[Principle]:
Analysis method based on the specificity and reversibility of binding reaction between antigen and antibody.
[Advantages and disadvantages]:
Simple operation, fast speed, low analysis cost. The sample size is small, the pretreatment is simple, the capacity is large, the instrumentalization degree is low, the detection sensitivity is high.
[Scope of application]:
On-site monitoring and screening of a large number of samples.

5. Introduction of our products

100001 - Beta Lactams Rapid Test Kit
100002 - BT Combo Rapid Test Kit
100003 - Beta Lactamase Test Kit
100015 - TriTest BTS Rapid Test Kit
100016 - TriTest BTM1 Rapid Test Kit
100017 - TriTest BTM Rapid Test Kit
100018 - QuaTest BTSC Rapid Test Kit
100019 - TriTest BTCex Rapid Test Kit
100021 - BCex Combo Rapid Test Kit