Topic
Tiamulin
About: Tiamulin is a research topic. Over the lifetime, 463 publications have been published within this topic receiving 7206 citations.
Papers published on a yearly basis
Papers
TL;DR: Overall, pleuromutilins and, in particular, lefamulin are characterized by potent activity against Gram-positive and fastidious Gram-negative pathogens as well as against mycoplasmas and intracellular organisms, such as Chlamydia spp.
Abstract: Pleuromutilins are antibiotics that selectively inhibit bacterial translation and are semisynthetic derivatives of the naturally occurring tricyclic diterpenoid pleuromutilin, which received its name from the pleuromutilin-producing fungus Pleurotus mutilus Tiamulin and valnemulin are two established derivatives in veterinary medicine for oral and intramuscular administration. As these early pleuromutilin drugs were developed at a time when companies focused on major antibacterial classes, such as the β-lactams, and resistance was not regarded as an issue, interest in antibiotic research including pleuromutilins was limited. Over the last decade or so, there has been a resurgence in interest to develop this class for human use. This has resulted in a topical derivative, retapamulin, and additional derivatives in clinical development. The most advanced compound is lefamulin, which is in late-stage development for the intravenous and oral treatment of community-acquired bacterial pneumonia and acute bacterial skin infections. Overall, pleuromutilins and, in particular, lefamulin are characterized by potent activity against Gram-positive and fastidious Gram-negative pathogens as well as against mycoplasmas and intracellular organisms, such as Chlamydia spp. and Legionella pneumophila Pleuromutilins are unaffected by resistance to other major antibiotic classes, such as macrolides, fluoroquinolones, tetracyclines, β-lactam antibiotics, and others. Furthermore, pleuromutilins display very low spontaneous mutation frequencies and slow, stepwise resistance development at sub-MIC in vitro. The potential for resistance development in clinic is predicted to be slow as confirmed by extremely low resistance rates to this class despite the use of pleuromutilins in veterinary medicine for >30 years. Although rare, resistant strains have been identified in human- and livestock-associated environments and as with any antibiotic class, require close monitoring as well as prudent use in veterinary medicine. This review focuses on the structural characteristics, mode of action, antibacterial activity, and resistance development of this potent and novel antibacterial class for systemic use in humans.
171 citations
TL;DR: It is inferred that tiamulin and valnemulin interact with the rRNA in the peptidyl transferase slot on the ribosomes in which they prevent the correct positioning of the CCA‐ends of tRNAs for peptide transfer.
Abstract: The pleuromutilin antibiotic derivatives, tiamulin and valnemulin, inhibit protein synthesis by binding to the 50S ribosomal subunit of bacteria. The action and binding site of tiamulin and valnemulin was further characterized on Escherichia coli ribosomes. It was revealed that these drugs are strong inhibitors of peptidyl transferase and interact with domain V of 23S RNA, giving clear chemical footprints at nucleotides A2058-9, U2506 and U2584-5. Most of these nucleotides are highly conserved phylogenetically and functionally important, and all of them are at or near the peptidyl transferase centre and have been associated with binding of several antibiotics. Competitive footprinting shows that tiamulin and valnemulin can bind concurrently with the macrolide erythromycin but compete with the macrolide carbomycin, which is a peptidyl transferase inhibitor. We infer from these and previous results that tiamulin and valnemulin interact with the rRNA in the peptidyl transferase slot on the ribosomes in which they prevent the correct positioning of the CCA-ends of tRNAs for peptide transfer.
163 citations
TL;DR: Key aspects of this antibacterial class are discussed and some insight is provided into the question of why it took half a century to develop a systemic pleuromutilin for human use is provided.
Abstract: In 1951, the first reference to the antibacterial substance pleuromutilin was made in a paper published in the Proceedings of the National Academy of Sciences. Researchers had identified several species of the mold genus Pleurotus that inhibited the growth of Staphylococcus aureus. The elucidation of the structure in 1962 led to the initiation of a development program at Sandoz, which was followed by the approval of tiamulin in 1979 for use in veterinary medicine. Although in 2007 retapamulin became the first pleuromutilin approved for topical use in humans, it was not until 2011, exactly 60 years after the first mention of the class, that a pleuromutilin antibiotic, BC-3781, could be tested successfully in a clinical phase II trial for systemic use in patients. This review will discuss key aspects of this antibacterial class and provide some insight into the question of why it took half a century to develop a systemic pleuromutilin for human use.
142 citations
Journal Article•
TL;DR: The key properties of pleuromutilin derivatives, designed primarily through modifications at the C(14) side chain, are presented, and the potential of these compounds in systemic therapy in humans is discussed.
Abstract: Pleuromutilins were discovered as natural-product antibiotics in 1950. Tiamulin was the first pleuromutilin compound to be approved for veterinary use in 1979, followed by valnemulin in 1999. It was not until 2007 that retapamulin became the first pleuromutilin approved for use in humans. However, retapamulin is limited to topical application. Recent advances in lead optimization have led to the synthesis of pleuromutilins that combine potent antibacterial activity with favorable pharmaceutical properties, making these compounds suitable for oral and intravenous delivery. Most pleuromutilins have an antibacterial spectrum that spans the common pathogens involved in both skin and respiratory tract infections. Two new pleuromutilins, BC-3205 and BC-7013 (both Nabriva Therapeutics AG), have entered clinical trials. In this review, the key properties of pleuromutilin derivatives, designed primarily through modifications at the C(14) side chain, are presented, and the potential of these compounds in systemic therapy in humans is discussed.
140 citations
TL;DR: Structural modification of the antibiotic pleuromutilin has afforded several derivatives with considerably enhanced activity against bacteria and mycoplasmas, and has permitted conclusions to be reached about structure-activity relationships.
Abstract: Structural modification of the antibiotic pleuromutilin has afforded several derivatives with considerably enhanced activity against bacteria and mycoplasmas, and has permitted conclusions to be reached about structure-activity relationships. The carbonyl group in the five-membered ring and the hydroxyl group at C11 seem to be essential for activity. The vinyl group can be hydrogenated without loss of activity. Chemical modification at C14 offers the most possibilities for achieving the best activity and solubility properties. Mutilin, and other compounds with a free OH at C14, are inactive. It was shown that mutilin esters of substituted thioglycolic acids had distinctly superior MIC values, especially in combination with a tertiary amino group in the side chain, the latter group of derivatives having MIC values better than pleuromutilin by a factor of more than 10. Further variation within this group led to the development of 14-deoxy-14-[(2-diethylaminoethyl) thioacetoxy]-mutilin hydrogen fumarate (81.723 hfu, tiamulin) for extensive investigation of its chemotherapeutic potential.
130 citations
Related Topics (5)
Performance Metrics
| Year | Papers |
|---|---|
| 2025 | 3 |
| 2024 | 9 |
| 2023 | 9 |
| 2022 | 22 |
| 2021 | 14 |
| 2020 | 19 |