Iboxamycin

Last updated
Iboxamycin
Iboxamycin.svg
Names
IUPAC name
(4S,5aS,8S,8aR)-N-[(1S,2S)-2-chloro-1-[(2R,3R,4S,5R,6R)-3,4,5-trihydroxy-6-methylsulfanyloxan-2-yl]propyl]-4-(2-methylpropyl)-3,4,5,5a,6,7,8,8a-octahydro-2H-oxepino[2,3-c]pyrrole-8-carboxamide
Identifiers
3D model (JSmol)
PubChem CID
  • InChI=1S/C22H39ClN2O6S/c1-10(2)7-12-5-6-30-19-13(8-12)9-24-15(19)21(29)25-14(11(3)23)20-17(27)16(26)18(28)22(31-20)32-4/h10-20,22,24,26-28H,5-9H2,1-4H3,(H,25,29)/t11-,12-,13-,14+,15-,16-,17+,18+,19+,20+,22+/m0/s1
    Key: JPCLUJPDWMBCAA-SUTQZAMLSA-N
  • C[C@@H]([C@H]([C@@H]1[C@@H]([C@@H]([C@H]([C@H](O1)SC)O)O)O)NC(=O)[C@@H]2[C@H]3[C@@H](C[C@@H](CCO3)CC(C)C)CN2)Cl
Properties
C22H39ClN2O6S
Molar mass 495.07 g·mol−1
Related compounds
Related compounds
Cresomycin
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Iboxamycin is a synthetic lincosamide or oxepanoprolinamide antibiotic. It binds to the bacterial ribosome in both Gram-negative and Gram-positive bacteria and it has been found to effective against bacteria which are resistant to other antibiotics that target the large ribosomal subunit. It was developed by combining an oxepano proline unit with the aminooctose residue of clindamycin. [1]

Iboxamycin is effective against ESKAPE bacteria, methicillin-resistant Staphylococcus aureus (MRSA), Enterococcus , Clostridioides difficile , [1] and Listeria monocytogenes , [2] indicating an extended spectrum when compared to clindamycin. [1] Isotopic labeling of iboxamycin with tritium indicated that it binds 70 times more tightly to the ribosome than clindamycin. [3]

Iboxamycin can be administered orally and is safe when administered to mice. [1] It is a bacteriostatic antibiotic. [1]

See also

Related Research Articles

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Macrolides are a class of mostly natural products with a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. The lactone rings are usually 14-, 15-, or 16-membered. Macrolides belong to the polyketide class of natural products. Some macrolides have antibiotic or antifungal activity and are used as pharmaceutical drugs. Rapamycin is also a macrolide and was originally developed as an antifungal, but has since been used as an immunosuppressant drug and is being investigated as a potential longevity therapeutic.

<span class="mw-page-title-main">Aminoglycoside</span> Antibacterial drug

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<span class="mw-page-title-main">Clindamycin</span> Antibiotic

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<i>Listeria</i> Genus of bacteria

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<span class="mw-page-title-main">Tigecycline</span> Chemical compound

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<span class="mw-page-title-main">Lincosamides</span> Group of antibiotics

Lincosamides are a class of antibiotics, which include lincomycin, clindamycin, and pirlimycin.

<span class="mw-page-title-main">Tetracycline antibiotics</span> Type of broad-spectrum antibiotic

Tetracyclines are a group of broad-spectrum antibiotic compounds that have a common basic structure and are either isolated directly from several species of Streptomyces bacteria or produced semi-synthetically from those isolated compounds. Tetracycline molecules comprise a linear fused tetracyclic nucleus to which a variety of functional groups are attached. Tetracyclines are named after their four ("tetra-") hydrocarbon rings ("-cycl-") derivation ("-ine"). They are defined as a subclass of polyketides, having an octahydrotetracene-2-carboxamide skeleton and are known as derivatives of polycyclic naphthacene carboxamide. While all tetracyclines have a common structure, they differ from each other by the presence of chloro, methyl, and hydroxyl groups. These modifications do not change their broad antibacterial activity, but do affect pharmacological properties such as half-life and binding to proteins in serum.

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EF-G is a prokaryotic elongation factor involved in mRNA translation. As a GTPase, EF-G catalyzes the movement (translocation) of transfer RNA (tRNA) and messenger RNA (mRNA) through the ribosome.

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A protein synthesis inhibitor is a compound that stops or slows the growth or proliferation of cells by disrupting the processes that lead directly to the generation of new proteins.

Streptogramin A is a group of antibiotics within the larger family of antibiotics known as streptogramins. They are synthesized by the bacteria Streptomyces virginiae. The streptogramin family of antibiotics consists of two distinct groups: group A antibiotics contain a 23-membered unsaturated ring with lactone and peptide bonds while group B antibiotics are depsipeptides. While structurally different, these two groups of antibiotics act synergistically, providing greater antibiotic activity than the combined activity of the separate components. These antibiotics have until recently been commercially manufactured as feed additives in agriculture, although today there is increased interest in their ability to combat antibiotic-resistant bacteria, particularly vancomycin-resistant bacteria.

<span class="mw-page-title-main">Solithromycin</span> Chemical compound

Solithromycin is a ketolide antibiotic undergoing clinical development for the treatment of community-acquired pneumonia and other infections.

<span class="mw-page-title-main">Bottromycin</span> Chemical compound

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<span class="mw-page-title-main">Cyclic di-AMP</span> Chemical compound

Cyclic di-AMP is a second messenger used in signal transduction in bacteria and archaea. It is present in many Gram-positive bacteria, some Gram-negative species, and archaea of the phylum Euryarchaeota.

Odilorhabdins are a class of natural antibacterial agents produced by the bacterium Xenorhabdus nematophila. Odilorhabdins act against both Gram-positive and Gram-negative pathogens, and were shown to eliminate infections in mouse models.

<span class="mw-page-title-main">Pyrrhocoricin</span> Peptide

Pyrrhocoricin is a 20-residue long antimicrobial peptide of the firebug Pyrrhocoris apterus.

<span class="mw-page-title-main">Oxepanoprolinamide</span> Class of chemical compounds

Oxepanoprolinamides are a class of antibiotics. They include iboxamycin. These drugs are fully synthetic. The molecules contain the aminooctose component of clindamycin. They were developed by Andrew G. Myers and Yury S. Polikanov. The structure contains an oxepane and a proline, with an amide group that increases rigidity.

Parvulin-like peptidyl-prolyl isomerase (PrsA), also referred to as putative proteinase maturation protein A (PpmA), functions as a molecular chaperone in Gram-positive bacteria, such as B. subtilis, S. aureus, L. monocytogenes and S. pyogenes. PrsA proteins contain a highly conserved parvulin domain that contains peptidyl-prolyl cis-trans isomerase (PPIase) activity capable of catalyzing the bond N-terminal to proline from cis to trans, or vice versa, which is a rate limiting step in protein folding. PrsA homologs also contain a foldase domain suspected to aid in the folding of proteins but, unlike the parvulin domain, is not highly conserved. PrsA proteins are capable of forming multimers in vivo and in vitro and, when dimerized, form a claw-like structure linked by the NC domains. Most Gram-positive bacteria contain only one PrsA-like protein, but some organisms such as L. monocytogenes, B. anthracis and S. pyogenes contain two PrsAs.

<span class="mw-page-title-main">Cresomycin</span> Chemical compound

Cresomycin is an experimental antibiotic. It binds to the bacterial ribosome in both Gram-negative and Gram-positive bacteria, and it has been found to be effective against multi-drug-resistant stains of Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. It belongs to the bridged macrobicyclic oxepanoprolinamide antibiotics, which have similarities with lincosamides antibiotics.

References

  1. 1 2 3 4 5 Mitcheltree, Matthew J.; Pisipati, Amarnath; Syroegin, Egor A.; Silvestre, Katherine J.; Klepacki, Dorota; Mason, Jeremy D.; Terwilliger, Daniel W.; Testolin, Giambattista; Pote, Aditya R.; Wu, Kelvin J. Y.; Ladley, Richard Porter; Chatman, Kelly; Mankin, Alexander S.; Polikanov, Yury S.; Myers, Andrew G. (2021). "A synthetic antibiotic class overcoming bacterial multidrug resistance". Nature. 599 (7885): 507–512. Bibcode:2021Natur.599..507M. doi:10.1038/s41586-021-04045-6. ISSN   0028-0836. PMC   8549432 . PMID   34707295.
  2. Brodiazhenko, Tetiana; Turnbull, Kathryn Jane; Wu, Kelvin J Y; Takada, Hiraku; Tresco, Ben I C; Tenson, Tanel; Myers, Andrew G; Hauryliuk, Vasili (17 June 2022). "Synthetic oxepanoprolinamide iboxamycin is active against Listeria monocytogenes despite the intrinsic resistance mediated by VgaL/Lmo0919 ABCF ATPase". JAC-Antimicrobial Resistance. 4 (3): dlac061. doi:10.1093/jacamr/dlac061. ISSN   2632-1823. PMC   9204466 . PMID   35733912.
  3. Wu, Kelvin J.Y.; Klepacki, Dorota; Mankin, Alexander S.; Myers, Andrew G. (July 2023). "A method for tritiation of iboxamycin permits measurement of its ribosomal binding". Bioorganic & Medicinal Chemistry Letters. 91: 129364. doi:10.1016/j.bmcl.2023.129364. PMC   10408240 . PMID   37295615.