Paromomycine

Therapeutic Use in Parasitic Infections

Leishmaniasis Treatment

Paromomycin has been extensively studied for its efficacy against leishmaniasis, a disease caused by protozoan parasites transmitted by sandflies. It is particularly noted for its effectiveness in both cutaneous and visceral forms of the disease.

• Cutaneous Leishmaniasis : A meta-analysis revealed that paromomycin treatment had a success rate approximately 2.79 times higher than that of placebo treatments . In a study involving topical applications, paromomycin demonstrated a cure rate close to 80% against Leishmania panamensis species .
• Visceral Leishmaniasis : A Phase IIIb clinical trial assessed intramuscular injections of paromomycin at 11 mg/kg for 21 days in Bangladeshi patients. The results indicated significant clinical responses, with many patients showing resolution of symptoms and no new signs six months post-treatment .

Research on Glioblastoma

Recent studies have explored the potential of paromomycin as a therapeutic agent for glioblastoma, a highly aggressive brain tumor. A study published in December 2024 investigated its effects on SUMOylation pathways mediated by histone deacetylase 1 (HDAC1) in glioblastoma cells.

• Mechanism of Action : Paromomycin was identified as a potential HDAC1 inhibitor through molecular docking analysis. In vitro assays showed that it significantly reduced cell viability and migration in glioblastoma cells while modulating SUMO1 expression and decreasing IGF1R nuclear translocation .
• Clinical Implications : These findings suggest that paromomycin may offer a novel approach to glioblastoma treatment by targeting specific molecular pathways, warranting further clinical investigation.

Broader Applications

Beyond its use in treating leishmaniasis and glioblastoma, paromomycin has been investigated for other conditions:

• Amebiasis : Paromomycin is effective against Entamoeba histolytica, the causative agent of amebic dysentery, providing an alternative to more toxic treatments such as metronidazole .
• Cryptosporidiosis : This compound has also shown promise against Cryptosporidium infections, particularly in immunocompromised patients, due to its low toxicity profile compared to traditional therapies .

Target of Action

Paromomycin primarily targets the 16S ribosomal RNA of bacteria . This RNA is a component of the small (30S) subunit of the bacterial ribosome, which is involved in protein synthesis .

Mode of Action

Paromomycin inhibits protein synthesis by binding to the 16S ribosomal RNA . The bacterial proteins are synthesized by ribosomal RNA complexes, which are composed of two subunits, a large subunit (50S) and a small (30S) subunit, forming a 70S ribosomal subunit . The tRNA binds to the top of this ribosomal structure . By binding to the 16S ribosomal RNA, paromomycin interferes with this process, leading to the production of defective proteins .

Biochemical Pathways

It is known that the drug interferes with protein synthesis, which is a crucial process for bacterial survival . This interference leads to the production of defective proteins, which can disrupt various cellular functions and eventually lead to bacterial death .

Pharmacokinetics

Paromomycin is poorly absorbed in the gastrointestinal tract . This characteristic makes it particularly useful for treating intestinal infections, as the drug remains in the gut where it can act directly on the infecting organisms . The drug is excreted in feces .

Result of Action

The primary result of paromomycin’s action is the death of the bacteria. By inhibiting protein synthesis, paromomycin causes the production of defective proteins. The accumulation of these defective proteins disrupts various cellular functions, leading to bacterial death .

Action Environment

The action of paromomycin is influenced by the environment in which it is used. For instance, in the gastrointestinal tract, where it is poorly absorbed, paromomycin can act directly on the infecting organisms . .

Biochemical Properties

Paromomycin inhibits protein synthesis by binding to 16S ribosomal RNA . This interaction with the ribosomal RNA complexes, which are composed of two subunits, disrupts the formation of bacterial proteins . The nature of these interactions is such that it closely parallels the in vitro and in vivo antibacterial action of neomycin .

Cellular Effects

Paromomycin has a broad spectrum of activity against various types of cells, including Gram-negative and Gram-positive bacteria . It increases the error rate in ribosomal translation, leading to the production of defective polypeptide chains . This continuous production of defective proteins eventually leads to bacterial death .

Molecular Mechanism

The mechanism of action of Paromomycin involves its binding to a RNA loop, where residues A1492 and A1493 are usually stacked, and expels these two residues . These two residues are involved in the detection of correct Watson-Crick pairing between the codon and anti-codon .

Temporal Effects in Laboratory Settings

The effects of Paromomycin over time in laboratory settings have not been extensively studied. It is known that the most common adverse effects associated with Paromomycin sulfate are abdominal cramps, diarrhea, heartburn, nausea, and vomiting . Long-term use of Paromomycin increases the risk for bacterial or fungal infection .

Dosage Effects in Animal Models

The effects of Paromomycin vary with different dosages in animal models . For example, it has been shown to be effective at a dosage of 50mg/kg/day or more for ileal infection and 200mg/kg/day or more for caecal infection . The effect was thus shown to differ according to the anatomical site of the infection .

Metabolic Pathways

The metabolic pathways that Paromomycin is involved in primarily relate to its role as an aminoglycoside antibiotic. It inhibits protein synthesis by binding to 16S ribosomal RNA

Transport and Distribution

Paromomycin is poorly absorbed after oral administration, with almost 100% of the drug recoverable in the stool This suggests that its transport and distribution within cells and tissues are limited

Paromomycin is produced by the bacterium Streptomyces rimosus var. paromomycinus . The industrial production of paromomycin typically involves fermentation processes. Solid-state fermentation has been shown to be a promising method for producing paromomycin, offering advantages such as cost reduction of raw materials, less energy consumption, and reduced wastewater discharge . The optimization of environmental conditions, such as pH, temperature, and inoculum size, can significantly enhance the yield of paromomycin .

Paromomycin undergoes various chemical reactions, including oxidation and substitution reactions. The compound contains oxidizable groups such as amines and hydroxyls, which can be detected electrochemically . Common reagents used in these reactions include oxidizing agents and derivatization agents for detection purposes. The major products formed from these reactions depend on the specific conditions and reagents used.

Paromomycin is similar to other aminoglycoside antibiotics such as neomycin and streptomycin . it has unique properties that make it effective against a broader range of parasitic infections. Unlike some other aminoglycosides, paromomycin is poorly absorbed in the gastrointestinal tract, making it particularly useful for treating intestinal infections . Additionally, paromomycin has been shown to have fewer systemic side effects compared to pentavalent antimony compounds used in the treatment of leishmaniasis .

Similar Compounds

• Neomycin
• Streptomycin
• Gentamicin
• Tobramycin

Paromomycin’s unique properties and broad-spectrum activity make it a valuable antibiotic in both clinical and research settings.

Paromomycin is an aminoglycoside antibiotic primarily recognized for its effectiveness against various parasitic infections, particularly those caused by Leishmania and Cryptosporidium. Its mechanism of action primarily involves the inhibition of protein synthesis by binding to the ribosomal RNA of target organisms. This article explores the biological activity of paromomycin, highlighting its therapeutic applications, mechanisms, and clinical findings.

Paromomycin exerts its antimicrobial effects by binding to the 16S ribosomal RNA component of the 30S ribosomal subunit in bacteria and protozoa. This binding leads to misreading of mRNA and the production of defective polypeptides, ultimately resulting in cell death. The antibiotic demonstrates a differential affinity for ribosomal components between protozoan and mammalian cells, which underlies its selective toxicity:

• Protozoan Ribosomes : Paromomycin binds strongly, inhibiting protein synthesis significantly.
• Mammalian Ribosomes : The interaction is minimal, leading to little effect on mammalian protein synthesis .

Efficacy Against Leishmaniasis

Recent studies have demonstrated paromomycin's effectiveness in treating cutaneous leishmaniasis. In a clinical trial conducted in Iran, paromomycin showed a success rate of treatment that was 2.79 times higher than that of placebo treatments. The meta-analysis indicated that paromomycin was significantly more effective compared to other interventions like photodynamic therapy (PDT) and intralesional meglumine antimoniate (MA) .

Table 1: Success Rates of Paromomycin in Treating Leishmaniasis

Clinical Applications

Paromomycin is used not only for leishmaniasis but also as a treatment for intestinal amebiasis and as an adjunct therapy for hepatic encephalopathy. Its administration can be oral or intramuscular, with intramuscular injections being particularly effective in visceral leishmaniasis (VL) cases.

In a Phase IIIb trial in Bangladesh, paromomycin administered at a dose of 11 mg/kg intramuscularly once daily for 21 days proved effective against VL, demonstrating significant clinical improvement in patients .

Case Studies

• Topical Application : A study involving topical application of a 15% paromomycin formulation showed a cure rate of 77.5% among patients with Leishmania braziliensis cutaneous leishmaniasis .
• Intramuscular Efficacy : Another investigation highlighted that PMIM (Paromomycin IM Injection) was effective and safe for treating VL, with a notable resolution of symptoms at the end of treatment and sustained clinical response six months post-treatment .
• Cryptosporidiosis : In patients with AIDS suffering from cryptosporidiosis, paromomycin exhibited modest activity, offering some therapeutic benefit where other treatments failed .

Safety Profile

While generally well-tolerated, paromomycin can cause side effects such as nephrotoxicity and ototoxicity, particularly at higher doses or prolonged use. Monitoring is essential during treatment to mitigate potential adverse effects .