What are beta-lactam antibiotics?

The most ancient and widely used class of antibiotics, beta-lactams are still very much in use today. Beta-lactams were generatedd by isolating molds, particularly Penicillium chrysogenum, and were first employed for medicinal purposes in human beings. Due to their vast variety of possible uses in healthcare settings, antibiotics belonging to the beta-lactam family are extensively employed and are regarded one of the most often prescribed categories of drugs. Their emergence in the 1930s signified a pivotal moment in combating bacterial-induced infectious illnesses.

In the fight against gram-positive bacteria, beta-lactam antibiotics are considered to be among the most effective medications. The reason for this is that these bacteria possess a dense peptidoglycan layer, which serves as the main focus of several beta-lactam antibiotics. Consequently, this is the cause for the occurrence. These antibiotics may be effective against gram-negative bacteria, but the outer membrane of these bacteria can prevent many beta-lactam antibiotics from entering, allowing certain bacteria to naturally develop resistance to the antibiotics. Nevertheless, there exist beta-lactam antibiotics specifically engineered to overcome this barrier.

Beta-lactam antibiotics examples

All beta-lactam antibiotics, from a pharmacological standpoint, have a ring structure with three carbon atoms and one nitrogen atom that is very reactive (see image below). This class includes:

• Penicillins. An essential component of these antibiotics, with the suffix-cillin being present in most of them, is 6-aminopenicillanic acid, which includes a thiazolidine ring, a lactam ring, and other side chains. This class includes ureidopenicillins, aminopenicillins, carboxypenicillins, beta-lactamase-resistant agents, and natural penicillins.
• Cephalosporins. Core components of these compounds include 7-aminocephalosporanic acid, while side chains comprise 3,6-dihydro-2 H-1,3-thiazane rings. Traditional wisdom holds that there are five generations or classes of cephalosporins, although not everyone adheres to this division.
• Carbapenems. Their primary composition consists of a carbapenem molecule linked to a beta-lactam ring, which provides defense against the majority of beta-lactamases. However, it is important to note that resistance to these compounds is a notable concern, primarily observed in gram-negative pathogens such as Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. These pathogens produce various types of beta-lactamases, specifically known as carbapenemases.
• Monobactams. The beta-lactam ring is isolated and not connected to any other ring.
• Beta-lactamase inhibitors. Their main mechanism of action is to deactivate serine beta-lactamases, which are enzymes responsible for hydrolyzing and deactivating the beta-lactam ring, particularly in gram-negative bacteria. The medicines mentioned include beta-lactamase inhibitors, including clavulanic acid, sulbactam, and tazobactam, which are the first-generation inhibitors. Additionally, there are newer inhibitors called avibactam and vaborbactam, which are effective against carbapenemase enzymes such as Klebsiella pneumoniae carbapenemase (KPC).

Actinomycetes generate natural β-lactam antibiotics and β-lactamase inhibitors. (De Simeis D., et al., 2021)

Beta-lactam antibiotics at BOC Sciences

Beta-lactam antibiotics mechanism of action

Peptidoglycan, or murein, is a vital element of the bacterial cell wall that provides it with mechanical stability. This component is preserved to a significant degree and may be found in the cell membranes of both gram-positive and gram-negative bacteria. Peptidoglycan has significant thickness in gram-positive bacteria, including a minimum of 10 layers. In contrast, it is considerably thinner in gram-negative bacteria, consisting of just one or two layers. Peptidoglycan is composed of glycan chains that are made up of N-acetylglucosamine and N-acetylmuramic acid di-saccharide subunits. The N-acetylmuramic part is linked to pentapeptide or tetrapeptide stems that are highly conserved, specifically consisting of l-alanine-d-isoglutamine-l-lysine-d-alanine-[d-alanine].

Beta-lactam antibiotics impede the last step of peptidoglycan production by binding an acyl group to the transpeptidase enzyme, which is responsible for linking peptides and constructing peptidoglycan. Penicillin-binding proteins (PBPs) serve as the particular recipients of beta-lactam antibiotics. The substance's binding interferes with the final transpeptidation process, resulting in a loss of capacity to survive and the breakdown of the bacterial cell. This is accomplished by autolytic processes that take place within the cell.

Types of beta-lactam antibiotics

According to chemical analysis, four primary groups of naturally occurring β-lactams are identified, with each group including a cyclic amide with four members. The bacterial antibiotic penicillin has a β-lactam ring fused with a five-membered ring containing a sulfur atom, whereas cephalosporins have a β-lactam ring fused with a six-membered unsaturated ring also including a sulfur atom, and carbapenems have an unsaturated five-membered ring free of heteroatoms. The β-lactam ring is the sole component found in monobactams (see image below).

One must take into consideration the fact that food might influence oral absorption when the medication is taken orally. In addition, the absorption of some compounds, such as cefuroxime and cefpodoxime, is reduced when H2 blockers or nonabsorbable antacids are taken alongside the patient. Several alternative routes are available for the administration of these medications. An oral dosage of penicillin V, either thirty minutes before a meal or two hours after it, is the most effective method of delivery. Both benzathine and procaine are considered to be parenteral formulations of penicillin G. The dosage of penicillin G benzathine is once per month since it has a longer half-life than other antibiotics. Penicillin G procaine is administered once daily since it has a shorter half-life than other antibiotics. No intravenous administration of either substance is recommended in order to prevent major toxicity. There are oral and parenteral formulations of penicillins that are resistant to penicillinase. These penicillins include oxacillin, cloxacillin, and dicloxacillin. Both amoxicillin and ampicillin are available in parenteral and oral formulations; however, amoxicillin is more commonly used orally. Aminopenicillins are called aminopenicillins. Piperacillin is the only known antipseudomonal penicillin that may be administered through the parenteral route. It is possible to administer certain cephalosporins intramuscularly or intravenously, although the majority of cephalosporins are rapidly absorbed after being taken orally.

Due to the fact that beta-lactam antibiotics exhibit a time-dependent effect on bacterial eradication (the length of time that the pathogen is exposed to the antibiotic is critical for bacterial eradication), continuous infusions of these antibiotics may offer benefits over the more conventional intermittent bolus doses. The treatment strategy in question is extremely successful, particularly in situations when the pathogens in question exhibit greater minimum inhibitory concentrations (MIC). As a result, the period that free drug concentrations persist over the minimum inhibitory concentration (fT>MIC) becomes a more accurate predictor of killing.

Base structural nucleus of β-lactam antibiotics. (De Simeis D., et al., 2021)

References

1. Pandey N., et al., Beta lactam antibiotics, 2019.
2. De Simeis D., et al., Actinomycetes: A never-ending source of bioactive compounds—An overview on antibiotics production Antibiotics, 2021, 10(5): 483.