Lactimidomycin

Natural glutarimide-containing translation elongation inhibitor from Streptomyces

Lactimidomycin
Chemical nomenclature
IUPAC name	4-[(E,2R,5S)-2-hydroxy-5-methyl-7-[(2R,3S,4Z,6E,10E)-3-methyl-12-oxo-1-oxacyclododeca-4,6,10-trien-2-yl]-4-oxooct-6-enyl]piperidine-2,6-dione
Routes	Experimental/research use
Legal status	Research compound; not approved as a therapeutic drug
Identifiers
CAS Number	134869-15-1
PubChem	11669726
ChemSpider	9844457
ChEMBL	1221911
Chemical data
Chemical formula	C26H35N1O6
Molecular weight	457.558
SMILES	N2C(=O)CC(CC2=O)CC(O)CC(=O)C(C)\C=C(/C)\C1OC(=O)C=CCCC=CC=CC1C
InChI	1S/C26H35NO6/c1-17-10-8-6-4-5-7-9-11-25(32)33-26(17)19(3)12-18(2)22(29)16-21(28)13-20-14-23(30)27-24(31)15-20/h4,6,8-12,17-18,20-21,26,28H,5,7,13-16H2,1-3H3,(H,27,30,31)/b6-4+,10-8-,11-9+,19-12+/t17-,18-,21+,26+/m0/s1
InChIKey	OYOKHBHOTQDIPM-BRHOHSSQSA-N

Lactimidomycin is a naturally occurring glutarimide-containing macrolide antibiotic and experimental protein synthesis inhibitor originally isolated from the actinomycete bacterium Streptomyces amphibiosporus. It is best known as a potent inhibitor of eukaryotic translation elongation and as a research tool for studying ribosome function, translation initiation, translation elongation, and ribosome profiling."Lactimidomycin, a new glutarimide group antibiotic. Production, isolation, structure and biological activity".The Journal of Antibiotics.1992;45(9)

1433-1441.PMID:1429229."Inhibition of eukaryotic translation elongation by cycloheximide and lactimidomycin".Nature Chemical Biology.2010;6(3)

209-217.doi:10.1038/nchembio.304.PMID:20118940.PMC:2831214.

Although lactimidomycin has shown experimental antifungal, antiviral, and antiproliferative activity in laboratory studies, it is not an approved medication for treatment of cancer, viral infection, fungal infection, or any human disease. Its importance is primarily in natural product chemistry, chemical biology, ribosome biology, antiviral research, and drug discovery.

Overview

Lactimidomycin belongs to a family of glutarimide-containing natural products that also includes cycloheximide, migrastatin, and isomigrastatin-related compounds. These molecules are notable because the glutarimide group can interact with the eukaryotic ribosome and interfere with protein synthesis.

Unlike many conventional antibiotics that target bacterial ribosomes, lactimidomycin acts mainly on the eukaryotic ribosome. This makes it toxic to eukaryotic cells and limits its direct therapeutic use, but it also makes it valuable as a laboratory probe of eukaryotic translation.

Chemical class and structure

Lactimidomycin is a complex natural product containing both a glutarimide moiety and an unsaturated macrocyclic lactone ring.

• Glutarimide - A cyclic imide group also found in cycloheximide and related translation inhibitors.
• Macrolide - A compound containing a large macrocyclic lactone ring.
• Lactone - Cyclic ester group present in the macrocycle.
• Polyketide - Biosynthetic class of many Streptomyces-derived natural products.
• Unsaturated compound - Lactimidomycin contains multiple carbon-carbon double bonds.
• Stereochemistry - The molecule contains several stereocenters important for biological activity.
• Natural product - Compound produced by a living organism and studied for biological activity.

Source organism

Lactimidomycin was isolated from Streptomyces amphibiosporus, an actinomycete bacterium. Species of Streptomyces are a major source of clinically important antibiotics, antifungals, immunosuppressants, anticancer agents, and biochemical research tools.

• Streptomyces amphibiosporus - Reported producing organism.
• Actinomycete - Bacterial group rich in secondary metabolites.
• Secondary metabolite - Nonessential metabolite often involved in ecological competition.
• Fermentation - Process used to cultivate microbial natural products.
• Antibiotic discovery - Field in which Streptomyces natural products are especially important.

Discovery

Lactimidomycin was first reported in 1992 as a new glutarimide-group antibiotic from Streptomyces amphibiosporus. The original report described its production, isolation, structure, and biological activity."Lactimidomycin, a new glutarimide group antibiotic. Production, isolation, structure and biological activity".The Journal of Antibiotics.1992;45(9)

1433-1441.PMID:1429229.

Subsequent biosynthetic studies identified related lactimidomycin congeners and helped clarify the natural product pathway in Streptomyces amphibiosporus."New lactimidomycin congeners shed insight into lactimidomycin biosynthesis in Streptomyces amphibiosporus".Organic Letters.2007;9(25)

5183-5186.PMID:17997563.

Mechanism of action

Lactimidomycin inhibits eukaryotic translation by interfering with the elongation phase of protein synthesis. It binds at or near the E site of the large ribosomal subunit and blocks ribosomal translocation, thereby preventing normal movement of transfer RNA and messenger RNA through the ribosome."Inhibition of eukaryotic translation elongation by cycloheximide and lactimidomycin".Nature Chemical Biology.2010;6(3)

209-217.doi:10.1038/nchembio.304.PMID:20118940.PMC:2831214.

• Eukaryotic translation - Protein synthesis process targeted by lactimidomycin.
• Translation elongation - Stage of protein synthesis inhibited by the compound.
• Ribosome - Molecular machine that translates mRNA into protein.
• E site - Ribosomal exit site for deacylated tRNA.
• Translocation - Ribosomal movement along mRNA during elongation.
• Transfer RNA - RNA molecule that carries amino acids during translation.
• Messenger RNA - Template read by the ribosome.
• Protein synthesis inhibitor - Drug or compound that blocks protein production.
• Cycloheximide - Related eukaryotic translation inhibitor with overlapping ribosomal binding features.

Structural studies of eukaryotic ribosome inhibitors showed how lactimidomycin and related molecules inhibit the ribosome, helping explain their potent effects on protein synthesis."Structural basis for the inhibition of the eukaryotic ribosome".Nature.2014;513(7519)

517-522.doi:10.1038/nature13737.PMID:25209664.

Research uses

Because lactimidomycin preferentially traps ribosomes near translation initiation sites under certain experimental conditions, it has been used in ribosome profiling and related methods to study the beginning of protein synthesis.

• Ribosome profiling - Genome-wide method for mapping ribosome-protected mRNA fragments.
• Translation initiation site - Site where ribosomes begin protein synthesis.
• Global translation initiation sequencing - Method using lactimidomycin and cycloheximide to map initiation and elongation events.
• Open reading frame - Region of RNA translated into protein.
• Upstream open reading frame - Regulatory translated region upstream of a main coding sequence.
• Proteogenomics - Integration of proteomic and genomic data.
• Chemical biology - Use of small molecules to probe biological processes.
• Functional genomics - Genome-wide study of gene function.
• Translatome - Set of RNAs being actively translated.

A 2012 study used lactimidomycin in global translation initiation sequencing to map translation initiation sites in mammalian cells with high resolution."Global mapping of translation initiation sites in mammalian cells at single-nucleotide resolution".Proceedings of the National Academy of Sciences of the United States of America.2012;109(37)

E2424-E2432.doi:10.1073/pnas.1207846109.PMID:22927429.PMC:3443142.

Biological activity

Antiproliferative activity

Lactimidomycin has shown potent antiproliferative activity against tumor cell lines in laboratory studies. This activity is consistent with its ability to inhibit eukaryotic protein synthesis, a process essential for cell growth and proliferation."Inhibition of eukaryotic translation elongation by cycloheximide and lactimidomycin".Nature Chemical Biology.2010;6(3)

209-217.doi:10.1038/nchembio.304.PMID:20118940.PMC:2831214.

However, inhibition of host-cell protein synthesis is also a major toxicity concern. Therefore, lactimidomycin is not used as a cancer drug in clinical practice.

Antiviral activity

Lactimidomycin has shown broad-spectrum antiviral activity in cell culture against several RNA viruses. A 2016 study reported activity against dengue virus and other RNA viruses, including Kunjin virus, Modoc virus, vesicular stomatitis virus, and poliovirus."Lactimidomycin is a broad-spectrum inhibitor of dengue and other RNA viruses".Antiviral Research.2016;128

57-62.doi:10.1016/j.antiviral.2016.02.005.PMID:26872864.PMC:4850914.

The antiviral mechanism is believed to involve inhibition of translation, a host-cell process required for viral protein production. Because it targets a host process, lactimidomycin can inhibit multiple viruses in vitro, but host toxicity limits direct clinical applicability.

Antifungal and antibiotic activity

The original discovery report described lactimidomycin as a glutarimide-group antibiotic with biological activity. Because it primarily inhibits eukaryotic translation, activity against fungi and other eukaryotic organisms is biologically plausible. It is not used clinically as an antifungal or antibacterial drug.

Biosynthesis

Lactimidomycin is a polyketide-derived natural product. Biosynthetic studies have identified related congeners and provided insight into the enzymatic assembly of the macrolide structure in Streptomyces amphibiosporus."New lactimidomycin congeners shed insight into lactimidomycin biosynthesis in Streptomyces amphibiosporus".Organic Letters.2007;9(25)

5183-5186.PMID:17997563.

• Polyketide synthase - Enzyme system often responsible for complex natural product assembly.
• Biosynthetic gene cluster - Cluster of genes encoding enzymes for natural product production.
• Congener - Structurally related natural product.
• Structure-activity relationship - Study of how chemical structure affects biological activity.
• Streptomyces - Bacterial genus known for complex secondary metabolism.

Total synthesis

Lactimidomycin has attracted interest from synthetic chemists because of its complex structure, stereochemistry, glutarimide moiety, and unsaturated 12-membered lactone ring. Several total synthesis, formal synthesis, and analogue synthesis approaches have been reported.

• Total synthesis - Complete chemical synthesis of a natural product from simpler compounds.
• Formal total synthesis - Synthesis of a known intermediate that has already been converted to the target molecule.
• Horner-Wadsworth-Emmons reaction - Olefination reaction used in some synthetic strategies.
• Macrocyclization - Formation of the macrocyclic ring.
• Stereoselective synthesis - Chemical synthesis controlling stereochemistry.
• Analogue synthesis - Preparation of related compounds to study function or improve properties.

Notable synthetic studies include concise total synthesis, macrocyclization-based approaches, and synthesis of analogues for biological evaluation."Concise total synthesis of the potent translation and cell migration inhibitor lactimidomycin".Journal of the American Chemical Society.2010;132(40)

14064-14066.doi:10.1021/ja107141p.PMID:20831202."Synthesis of eukaryotic translation elongation inhibitor lactimidomycin via Zn(II)-mediated Horner-Wadsworth-Emmons macrocyclization".Organic Letters.2013;15(12)

2998-3001.doi:10.1021/ol401186f.PMID:23731327."Formal total synthesis of lactimidomycin".Organic Letters.2013;15(12)

3002-3005.doi:10.1021/ol401214f.PMID:23731346."Synthesis and biological evaluation of lactimidomycin and its analogues".Chemistry: A European Journal.2015;21(52)

19159-19167.doi:10.1002/chem.201503527.PMID:26577990.

Relationship to related compounds

Lactimidomycin is structurally and mechanistically related to several glutarimide-containing or translation-inhibiting natural products.

• Cycloheximide - Classic eukaryotic translation elongation inhibitor.
• Migrastatin - Related glutarimide-containing natural product family member.
• Isomigrastatin - Structurally related compound with biological activity.
• Glutarimide antibiotic - Class containing glutarimide moieties.
• Translation inhibitor - Compound that blocks protein synthesis.
• Ribosome inhibitor - Compound that binds or interferes with ribosome function.

Comparative studies of cycloheximide and lactimidomycin have helped define a shared ribosomal binding pocket and clarify mechanisms of eukaryotic translation elongation inhibition."Inhibition of eukaryotic translation elongation by cycloheximide and lactimidomycin".Nature Chemical Biology.2010;6(3)

209-217.doi:10.1038/nchembio.304.PMID:20118940.PMC:2831214.

Safety and toxicology

Lactimidomycin is not approved for human or veterinary therapeutic use. Because it inhibits eukaryotic protein synthesis, it is expected to have significant cytotoxic potential. Published work on lactimidomycin is largely preclinical and laboratory-based.

• Cytotoxicity - Toxicity to cells due to inhibition of essential protein synthesis.
• Therapeutic index - Separation between effective and toxic doses; not established for clinical use.
• Preclinical research - Research before human clinical testing.
• Laboratory safety - Handling should follow institutional chemical safety procedures.
• No approved indication - Lactimidomycin is not an approved drug.
• Research chemical - Should not be used as a supplement or self-administered treatment.

Clinical status

As of 2026, lactimidomycin remains a research compound. It has not been approved by the U.S. Food and Drug Administration, European Medicines Agency, or other major regulatory bodies for clinical treatment of infectious disease, cancer, obesity, or any other medical condition.

No standard clinical dose, route of administration, pharmacokinetic profile, therapeutic range, or approved safety labeling exists for lactimidomycin.

Importance in biomedical research

Lactimidomycin is important because it provides a chemical tool for studying protein synthesis and because it demonstrates how host-targeted translation inhibitors can produce broad antiviral effects in vitro.

• Translation elongation research.
• Ribosome profiling.
• Translation initiation site mapping.
• Antiviral drug discovery.
• Cancer biology.
• Natural product biosynthesis.
• Synthetic organic chemistry.
• Structure-based drug design.
• Chemical genetics.
• Host-directed antiviral research.

Limitations

• Not clinically approved.
• Potential host-cell toxicity.
• Limited pharmacokinetic data.
• Limited in vivo efficacy data.
• Antiviral activity largely preclinical.
• Direct protein synthesis inhibition can affect normal cells.
• Synthesis is complex.
• Natural supply may be limited.
• Research use requires careful controls.

See also

• Ephedrine
• Cycloheximide
• Glutarimide
• Macrolide
• Lactone
• Streptomyces
• Protein synthesis inhibitor
• Eukaryotic translation
• Translation elongation
• Ribosome
• Ribosome profiling
• Natural product
• Polyketide
• Antiviral drug
• Dengue fever
• RNA virus
• Total synthesis
• Medicinal chemistry
• Chemical biology

Further reading

• "Lactimidomycin, a new glutarimide group antibiotic. Production, isolation, structure and biological activity".The Journal of Antibiotics.1992;45(9)

1433-1441.PMID:1429229.

• "New lactimidomycin congeners shed insight into lactimidomycin biosynthesis in Streptomyces amphibiosporus".Organic Letters.2007;9(25)

5183-5186.PMID:17997563.

• "Inhibition of eukaryotic translation elongation by cycloheximide and lactimidomycin".Nature Chemical Biology.2010;6(3)

209-217.doi:10.1038/nchembio.304.PMID:20118940.PMC:2831214.

• "Global mapping of translation initiation sites in mammalian cells at single-nucleotide resolution".Proceedings of the National Academy of Sciences of the United States of America.2012;109(37)

E2424-E2432.doi:10.1073/pnas.1207846109.PMID:22927429.PMC:3443142.

• "Structural basis for the inhibition of the eukaryotic ribosome".Nature.2014;513(7519)

517-522.doi:10.1038/nature13737.PMID:25209664.

• "Lactimidomycin is a broad-spectrum inhibitor of dengue and other RNA viruses".Antiviral Research.2016;128

57-62.doi:10.1016/j.antiviral.2016.02.005.PMID:26872864.PMC:4850914.

• "Total syntheses and biological reassessment of lactimidomycin, isomigrastatin and congener glutarimide antibiotics".Chemistry: A European Journal.2013;19(23)

7370-7383.doi:10.1002/chem.201300393.PMID:23595541.

• "Concise total synthesis of the potent translation and cell migration inhibitor lactimidomycin".Journal of the American Chemical Society.2010;132(40)

14064-14066.doi:10.1021/ja107141p.PMID:20831202.

• "Synthesis of eukaryotic translation elongation inhibitor lactimidomycin via Zn(II)-mediated Horner-Wadsworth-Emmons macrocyclization".Organic Letters.2013;15(12)

2998-3001.doi:10.1021/ol401186f.PMID:23731327.

• "Formal total synthesis of lactimidomycin".Organic Letters.2013;15(12)

3002-3005.doi:10.1021/ol401214f.PMID:23731346.

• "Synthesis and biological evaluation of lactimidomycin and its analogues".Chemistry: A European Journal.2015;21(52)

19159-19167.doi:10.1002/chem.201503527.PMID:26577990.

External links

• PubChem - Lactimidomycin
• ChEMBL - Lactimidomycin
• Nature Chemical Biology - Inhibition of eukaryotic translation elongation by cycloheximide and lactimidomycin
• PNAS - Global mapping of translation initiation sites
• Nature - Structural basis for inhibition of the eukaryotic ribosome
• Antiviral Research - Lactimidomycin as a broad-spectrum inhibitor of dengue and other RNA viruses

Types of antibacterials