What is Erythromycin?

Erythromycin is an antibiotic produced by the actinomycete Streptomyces erythreus, which was originally isolated from a soil sample from the city of Iloilo on the island of Panay in the Philippine Archipelago. First produced, purified, used clinically, and reported in 1952 by McGuire and his associates, erythromycin is one of a group of antibiotics with a macrocyclic lactone nucleus, known as macrolides.

Erythromycin is basic with a pKa of 8.6 and is relatively insoluble in water but readily soluble in organic solvents such as acetone or methyl or ethyl alcohol. It is susceptible to acid inactivation while in solution, which can be mitigated by making relatively insoluble salts of the base or by using a special enteric coating.

Erythromycin structure

Erythromycin is characterized by its complex macrolide ring structure, which is essential for its biological activity. The core of erythromycin is a 14-membered lactone ring, attached to two sugar moieties: desosamine and cladinose. The lactone ring features a series of hydroxyl groups and a keto group, which play crucial roles in the antibiotic's binding to bacterial ribosomes.

• 14-membered lactone ring

The core structure of erythromycin, providing the backbone for its antibiotic activity. The ring is large and contains multiple oxygen atoms, which are essential for binding to the bacterial ribosome.

• Desosamine sugar

An amino sugar that is crucial for the antibacterial activity of erythromycin. The desosamine moiety enhances the solubility and bioavailability of the antibiotic. It is involved in the binding of erythromycin to the 50S ribosomal subunit, contributing to the inhibition of protein synthesis.

• Cladinose

A neutral sugar that contributes to the overall stability and solubility of the molecule. The cladinose moiety is also involved in interactions with the ribosome, aiding in the antibiotic's binding and function.

Erythromycin mechanism of action

Erythromycin inhibits protein synthesis by binding to the 23S ribosomal RNA molecule in the 50S subunit of the bacterial ribosome, affecting elongation based on the nascent peptide's conformation. It can induce specific genes by stabilizing the ribosome-mRNA complex, particularly at rare codon sites, leading to ribosome stalling and mRNA protection. Humans have the 40S and 60S subunits and do not have 50S subunits, so erythromycin does not affect protein synthesis in human tissues.

• Binding and elongation inhibition

Erythromycin binds to the bacterial 50S ribosomal subunit, specifically near the peptidyl transferase center. Depending on the length and conformation of the nascent peptide, erythromycin can inhibit further elongation. Smaller macrolides like erythromycin produce only a partial block, affecting elongation based on the peptide's conformation.

• Partial block and peptide conformation

When erythromycin partially blocks the nascent peptide channel, certain peptides like oligophenylalanine can bypass the antibiotic, resulting in no inhibition. In contrast, peptides like oligolysine or most natural proteins are completely blocked, leading to the destabilization of the ribosome-peptidyl-tRNA complex.

• Intermediate case leading to induction

In an intermediate scenario, elongation of the nascent peptide chain is halted within the nascent peptide channel. This inhibits protein synthesis but stabilizes the ribosome-peptidyl-tRNA complex. This stabilization relative to the transcription time scale results in the induction of specific genes, like ermC or ermA, by protecting their mRNA from degradation.

• Role of rare codon usage

The presence of rare codons in the mRNA can maximize the probability of ribosome stalling at critical locations, like -IFVI- in the ermC leader peptide, which is necessary for induction. This stalling can mimic the effects of amino acid limitation, thereby slowing protein synthesis without the presence of antibiotics.

• MLS antibiotics and polysome stability

Macrolide-Lincosamide-Streptogramin (MLS) antibiotics that induce ermC stabilize the ribosome-mRNA complex, preventing degradation. Noninducing MLS antibiotics, however, lead to polysome breakdown and do not provide this stabilization, facilitating polysome disassembly.

• Abortive initiations and ribosome recycling

Erythromycin can cause the breakdown of polysomes, leading to abortive initiation cycles. This results in enhanced release of peptidyl-tRNA and destabilization of mRNA-bound ribosomes, with selective degradation of released 50S subunits, preventing their recycling.

• Leader peptide sequences

Only specific leader peptide sequences can support induction by erythromycin. These sequences, despite being structurally different, functionally mimic the critical sequence -IFVI- in ermC. Comparative analysis of these sequences could reveal systematic patterns and provide insights into the exceptional behavior of ribosomes in the presence of erythromycin.

Erythromycin's action is primarily bacteriostatic, meaning it inhibits bacterial growth without directly killing the bacteria. By preventing protein synthesis, erythromycin stops the production of essential proteins needed for bacterial growth and replication. This allows the host's immune system to combat the infection more effectively.

Macrolide antibiotics have anti-inflammatory and immunomodulatory actions. In preclinical studies, erythromycin inhibited neutrophil infiltration in the lungs and the periodontium. As a result, erythromycin protected against fatal pulmonary inflammation and inflammatory periodontal bone loss. Furthermore, because developmental endothelial locus-1 (DEL-1) levels are severely reduced in inflammatory conditions and aging, erythromycin's ability to upregulate DEL-1 may reveal a novel molecular mechanism responsible for erythromycin's anti-inflammatory and immunomodulatory actions.

Resistance can develop against erythromycin which occurs via modification of the 23S rRNA found in the 50S rRNA. The erythromycin cannot bind to the ribosome, and the bacteria can continue protein synthesis. Aside from being a bacteriostatic macrolide antibiotic, erythromycin is a pro-motility drug. It is an agonist to motilin, which increases motility in the gut.

Erythromycin class of antibiotics

Erythromycin belongs to the macrolide class of antibiotics, known for their macrocyclic lactone rings. This class includes other notable antibiotics such as azithromycin and clarithromycin. Macrolides are broadly effective against a range of gram-positive bacteria and some gram-negative bacteria, particularly those responsible for respiratory and soft tissue infections. The macrolide antibiotics share a common mechanism of action but differ in their pharmacokinetic profiles, spectra of activity, and side effect profiles.

Azithromycin vs. erythromycin

Azithromycin, a derivative of erythromycin, offers several pharmacokinetic advantages over its predecessor. Structurally, azithromycin differs by having a 15-membered ring instead of erythromycin's 14-membered ring, which confers greater acid stability and longer half-life. These structural modifications enable azithromycin to be administered less frequently, improving patient compliance. Erythromycin inhibits cytochrome P450 enzymes (particularly CYP3A4), which can lead to numerous drug interactions. Azithromycin has a lower potential for drug interactions. Additionally, azithromycin exhibits a broader spectrum of activity, particularly against gram-negative bacteria, and has better tissue penetration, making it a preferred choice for certain infections. However, erythromycin's role remains significant in specific contexts where its pharmacodynamic properties are particularly beneficial.

Tobramycin vs. erythromycin

Tobramycin, an aminoglycoside antibiotic, contrasts with erythromycin in both structure and mechanism of action. Tobramycin functions by binding to the 30S subunit of bacterial ribosomes, causing misreading of mRNA and inhibiting protein synthesis through a different pathway than erythromycin. Structurally, tobramycin consists of a 4,6-disubstituted 2-deoxystreptamine ring, lacking the macrolide's large lactone ring. The mechanisms of bacterial resistance differ. Erythromycin resistance often involves target site modification, efflux pumps, or enzymatic degradation. Tobramycin resistance may involve enzymatic inactivation or modifications that prevent drug binding. Tobramycin is often used for serious gram-negative infections (such as Pseudomonas aeruginosa), including those resistant to other antibiotics. Erythromycin is used for a variety of infections including respiratory infections, skin infections, and some gastrointestinal conditions.

Erythromycin at BOC Sciences

What is erythromycin used for?

Erythromycin is only effective for bacteria with active division. It is effective for most gram-positive bacteria, some gram-negative bacteria and some atypical pathogens. Erythromycin has strong antibacterial activity against Staphylococcus (including enzyme-producing strains) and streptococcus groups. It also has a good inhibitory effect on Treponema pallidum, Mycoplasma pneumoniae, Leptospira, Rickettsia and Chlamydia. At high concentration, erythromycin also has bactericidal effect on highly sensitive bacteria.

Therefore, it is often used to treat penicillin-resistant Staphylococcus aureus infection and those who are allergic to penicillin, and also used for various infections caused by the above sensitive bacteria. It can be used for treating oral infection caused by anaerobic bacteria and respiratory tract and urogenital tract infections caused by atypical pathogens such as mycoplasma pneumoniae and chlamydia pneumoniae. For diphtheria patients, erythromycin combined with diphtheria antitoxin is effective.

References

1. Weisblum, B. (1995). Insights into erythromycin action from studies of its activity as inducer of resistance. Antimicrobial Agents and Chemotherapy. 1995, 39(4): 797-805.
2. Scott Champney, W. The other target for ribosomal antibiotics: inhibition of bacterial ribosomal subunit formation. Infectious Disorders-Drug Targets (Formerly Current Drug Targets-Infectious Disorders). 2006, 6(4): 377-390.