High-throughput metabolomic analysis predicts mode of action of uncharacterized antimicrobial compounds

Science Translational Medicine
Mattia ZampieriUwe Sauer

Abstract

Rapidly spreading antibiotic resistance and the low discovery rate of new antimicrobial compounds demand more effective strategies for early drug discovery. One bottleneck in the drug discovery pipeline is the identification of the modes of action (MoAs) of new compounds. We have developed a rapid systematic metabolome profiling strategy to classify the MoAs of bioactive compounds. The method predicted MoA-specific metabolic responses in the nonpathogenic bacterium Mycobacterium smegmatis after treatment with 62 reference compounds with known MoAs and different metabolic and nonmetabolic targets. We then analyzed a library of 212 new antimycobacterial compounds with unknown MoAs from a drug discovery effort by the pharmaceutical company GlaxoSmithKline (GSK). More than 70% of these new compounds induced metabolic responses in M. smegmatis indicative of known MoAs, seven of which were experimentally validated. Only 8% (16) of the compounds appeared to target unconventional cellular processes, illustrating the difficulty in discovering new antibiotics with different MoAs among compounds used as monotherapies. For six of the GSK compounds with potentially new MoAs, the metabolome profiles suggested their ability to interfere with ...Continue Reading

References

Feb 2, 1966·Igaku to seibutsugaku. Medicine and biology·M Tsukamura
Nov 1, 1966·Journal of General Microbiology·M Tsukamura
Oct 24, 2001·American Journal of Respiratory and Critical Care Medicine·J A CamineroC Martin
Aug 31, 2002·Science·E RavaszA L Barabási
Oct 2, 2003·The Journal of Antimicrobial Chemotherapy·Elena BanfiCarlo Monti-Bragadin
Jan 14, 2004·Proceedings of the National Academy of Sciences of the United States of America·Guri GiaeverRonald W Davis
Feb 26, 2004·Antimicrobial Agents and Chemotherapy·Niilo KaldaluKim Lewis
Apr 27, 2004·Nature Genetics·Alon ZaslaverUri Alon
May 26, 2004·Chemistry & Biology·Lyle Burdine, Thomas Kodadek
Mar 3, 2007·Drug Discovery Today·Hanna Eckert, Jürgen Bajorath
Sep 4, 2007·Bioorganic & Medicinal Chemistry Letters·Todd E BowserMichael N Alekshun
Oct 21, 1960·Science·D J Rogers, T T Tanimoto
Sep 7, 2007·Cell·Michael A KohanskiJames J Collins
Sep 11, 2007·Nature Methods·Renate KönigSumit K Chanda
Dec 30, 2008·Artificial Intelligence in Medicine·Paolo TormeneMario Stefanelli
Jan 10, 2009·Nature Protocols·Da Wei HuangRichard A Lempicki
May 23, 2009·PloS One·Hany S GirgisSaeed Tavazoie
Nov 6, 2009·Molecular Biology of the Cell·Viktor M BoerJoshua D Rabinowitz
Aug 31, 2010·Nature Biotechnology·Christopher S HenryRick L Stevens
Oct 12, 2010·Autophagy·Francesco IorioNicola Brunetti-Pierri
Dec 22, 2010·Proceedings of the National Academy of Sciences of the United States of America·Valerie W C SooWayne M Patrick
Dec 28, 2010·Cell·Robert J NicholsCarol A Gross
Mar 19, 2011·Journal of Clinical Pharmacology·Philippe Grosjean, Saïk Urien
Oct 13, 2011·Molecular Systems Biology·Jeffrey D OrthBernhard Ø Palsson
Oct 20, 2011·ACS Chemical Biology·Steven HalouskaRobert Powers
Oct 26, 2011·Antimicrobial Agents and Chemotherapy·Valentina La RosaEdda De Rossi
Nov 24, 2011·Nature Communications·Stefano TizianiGiovanni Paternostro
Dec 20, 2011·Nature Chemical Biology·Christian LaggnerBrian K Shoichet
Feb 22, 2012·Nature Chemical Biology·Anna E GrzegorzewiczMary Jackson
Jan 12, 2013·ChemMedChem·Lluís BallellNicholas Cammack
Mar 20, 2013·Nature Chemical Biology·Monica SchenonePaul A Clemons
Apr 10, 2013·Bioorganic & Medicinal Chemistry Letters·Mark J Mitton-FryChristopher Zook
Jun 14, 2013·The Journal of Biological Chemistry·Cedric P OwensCelia W Goulding
Jun 20, 2013·The Journal of Biological Chemistry·Jun ZhengLuis R Camacho

❮ Previous
Next ❯

Citations

Jun 26, 2018·Angewandte Chemie·Markus LakemeyerStephan A Sieber
Oct 26, 2018·Small·Vadanasundari VedarethinamKun Qian
Mar 8, 2019·Frontiers in Microbiology·Julien BriffotauxBrigitte Gicquel
Jan 24, 2020·Scientific Reports·Natasha L Patel-MurrayErnest Fraenkel
Jul 19, 2018·Frontiers in Microbiology·Diana MachadoMarco Pieroni
Sep 11, 2019·Proceedings of the National Academy of Sciences of the United States of America·Zhe WangKyu Y Rhee
Apr 2, 2020·Proceedings of the National Academy of Sciences of the United States of America·Ove ØyåsMattia Zampieri
Feb 16, 2020·Nature Reviews. Genetics·Manon EckhardtNevan J Krogan
Feb 6, 2021·Metabolites·Dorothy Pei Shan Chang, Xue Li Guan
Feb 20, 2021·Frontiers in Microbiology·Alina MiniasJarosław Dziadek
Apr 14, 2020·Tuberculosis·Michelle H LarsenRichard T Robinson
Mar 19, 2021·Molecular Systems Biology·Michael ZimmermannLisa Maier
May 2, 2021·Journal of Hazardous Materials·Tharushi Prabha KeerthisingheMingliang Fang
May 24, 2020·Nature Communications·Erol S KavvasBernhard O Palsson
May 30, 2021·Nature Communications·Diego Antonio Fernandez FuentesMattia Zampieri
Jul 28, 2019·Microbiology Spectrum·Gabriel T MashabelaDigby F Warner
Jun 5, 2021·RSC Medicinal Chemistry·Katherine A Abrahams, Gurdyal S Besra
Jun 3, 2021·Antibiotics·Bernardo Ribeiro da CunhaCecília R C Calado
Jun 19, 2021·Computational and Structural Biotechnology Journal·Teresa Gil-GilJosé Luis Martínez
Aug 7, 2021·Frontiers in Digital Health·Allison J Lopatkin, Jason H Yang
Aug 17, 2021·Biotechnology and Bioengineering·Bernardo Ribeiro da CunhaCecília R C Calado
Nov 9, 2018·Journal of Agricultural and Food Chemistry·Kai On ChuChi Pui Pang
Aug 26, 2021·Computational and Structural Biotechnology Journal·Isin T SakalliogluRobert Powers
Sep 10, 2021·Annual Review of Pharmacology and Toxicology·André MateusMikhail M Savitski

❮ Previous
Next ❯

Related Concepts

Related Feeds

Antifungals

An antifungal, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis, cryptococcal meningitis, and others. Discover the latest research on antifungals here.

Antimicrobial Resistance

Antimicrobial resistance poses a significant threat to the continued successful use of antimicrobial agents for the treatment of bacterial infections.

Antimicrobial Resistance (ASM)

Antimicrobial resistance poses a significant threat to the continued successful use of antimicrobial agents for the treatment of bacterial infections.

Antifungals (ASM)

An antifungal, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis, cryptococcal meningitis, and others. Discover the latest research on antifungals here.

Related Papers

Combinatorial Chemistry & High Throughput Screening
Luciana ScottiEricsson Coy-Barrera
Medizinische Monatsschrift für Pharmazeuten
S Heinzl
© 2022 Meta ULC. All rights reserved