Lolamicin

Last updated
Lolamicin
Lolamicin.svg
Identifiers
3D model (JSmol)
ChemSpider
PubChem CID
  • InChI=1S/C24H20N4O/c1-16-9-21(10-17(2)27-16)23-14-26-28-24(23)20-7-4-8-22(12-20)29-15-19-6-3-5-18(11-19)13-25/h3-12,14H,15H2,1-2H3,(H,26,28)
    Key: CIXIQLLJOWEAKU-UHFFFAOYSA-N
  • CC1=CC(=CC(C)=N1)C1=CNN=C1C1=CC=CC(OCC2=CC(=CC=C2)C#N)=C1
Properties
C24H20N4O
Molar mass 380.451 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Lolamicin is an experimental antibiotic. [1] It targets Gram-negative bacteria without significantly affecting typical gut microbes. [2] Lolamicin was discovered by a team led by Paul J. Hergenrother at the University of Illinois Urbana-Champaign and was first reported in 2024. [1]

In a mouse model of bacterial infection, lolamicin was found to be especially effective against Escherichia coli , Klebsiella pneumoniae , and Enterobacter cloacae . [3]

Lolamicin works by interfering with the lipoprotein transport system of Gram-negative bacteria. [1]

Synthesis

Lolamicin is synthesized in five steps. Initially, methyl 3-hydroxybenzoate undergoes nucleophilic substitution with 3-(chloromethyl)benzonitrile in the presence of potassium carbonate, forming the corresponding ether. The ester is then hydrolyzed under basic conditions to yield the carboxylic acid. In a two-step process, the carboxylic acid is activated using PyBOP and reacted with N,O-dimethyl hydroxylamine hydrochloride to form the corresponding methoxamide. This intermediate is then subjected to condensation with 2,4,6-collidine under low-temperature conditions using lithium diisopropylamide (LDA), yielding a dimethylpyridine derivative. Finally, treatment with hydrazine monohydrate under reflux promotes cyclization to produce the final pyridine-pyrazole core structure of lolamicin. [1]

References

  1. 1 2 3 4 Muñoz, Kristen A.; Ulrich, Rebecca J.; Vasan, Archit K.; Sinclair, Matt; Wen, Po-Chao; Holmes, Jessica R.; Lee, Hyang Yeon; Hung, Chien-Che; Fields, Christopher J.; Tajkhorshid, Emad; Lau, Gee W.; Hergenrother, Paul J. (2024). "A Gram-negative-selective antibiotic that spares the gut microbiome". Nature. 630 (8016): 429–436. doi:10.1038/s41586-024-07502-0. PMID   38811738.
  2. ↑ "'Smart' antibiotic can kill deadly bacteria while sparing the microbiome". nature.com. May 29, 2024.
  3. ↑ "New antibiotic targets only gram-negative bacteria, sparing the gut". Chemical & Engineering News. June 1, 2024.
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