Slow-onset inhibition of the FabI enoyl reductase from francisella tularensis: residence time and in vivo activity.

ACS Chemical Biology
Hao LuPeter J Tonge

Abstract

Francisella tularensis is a highly virulent and contagious Gram-negative intracellular bacterium that causes the disease tularemia in mammals. The high infectivity and the ability of the bacterium to survive for weeks in a cool, moist environment have raised the possibility that this organism could be exploited deliberately as a potential biological weapon. Fatty acid biosynthesis (FAS-II) is essential for bacterial viability and has been validated as a target for the discovery of novel antibacterials. The FAS-II enoyl reductase ftuFabI has been cloned and expressed, and a series of diphenyl ethers have been identified that are subnanomolar inhibitors of the enzyme with MIC90 values as low as 0.00018 microg mL(-1). The existence of a linear correlation between the Ki and MIC values strongly suggests that the antibacterial activity of the diphenyl ethers results from direct inhibition of ftuFabI within the cell. The compounds are slow-onset inhibitors of ftuFabI, and the residence time of the inhibitors on the enzyme correlates with their in vivo activity in a mouse model of tularemia infection. Significantly, the rate of breakdown of the enzyme-inhibitor complex is a better predictor of in vivo activity than the overall thermod...Continue Reading

References

Aug 1, 1985·Journal of Clinical Microbiology·C N BakerC Thornsberry
Aug 26, 1998·Nature·L M McMurryS B Levy
Feb 27, 1999·Antimicrobial Agents and Chemotherapy·L M McMurryS B Levy
Apr 14, 1999·Nature·C W LevyJ B Rafferty
Jul 10, 1999·Journal of Molecular Biology·M J StewartC Kisker
Jan 3, 2001·Acta Crystallographica. Section D, Biological Crystallography·M D WinnG N Murshudov
Sep 7, 2001·Annual Review of Microbiology·J W Campbell, J E Cronan
Feb 28, 2003·The Journal of Biological Chemistry·Mack R KuoDavid A Fidock
Apr 18, 2003·Journal of Medicinal Chemistry·Mark A SeefeldWilliam F Huffman
Jul 5, 2003·The Journal of Biological Chemistry·Andrzej LewandowiczVern L Schramm
Sep 2, 2004·Nature Reviews. Drug Discovery·David C Swinney
Nov 20, 2004·Nature Reviews. Microbiology·Petra C F OystonRichard W Titball
Dec 2, 2004·Acta Crystallographica. Section D, Biological Crystallography·Paul Emsley, Kevin Cowtan
Dec 2, 2004·Acta Crystallographica. Section D, Biological Crystallography·E Krissinel, K Henrick
Jun 15, 2005·Annual Review of Biochemistry·Stephen W White Rock
Sep 27, 2005·Current Drug Targets. Infectious Disorders·Donald T Moir
Oct 22, 2005·Microbes and Infection·Anders Sjöstedt
Nov 8, 2005·The Journal of Immunology : Official Journal of the American Association of Immunologists·Catharine M Bosio, Steven W Dow
May 2, 2006·The Journal of Biological Chemistry·Yong-Mei ZhangCharles O Rock
Aug 5, 2006·Nature Reviews. Drug Discovery·Robert A CopelandThomas D Meek
Mar 10, 2007·Current Topics in Medicinal Chemistry·Peter J TongeRichard A Slayden
Jan 16, 2008·Accounts of Chemical Research·Hao Lu, Peter J Tonge
Apr 17, 2008·Biochemistry·Peter J Tummino, Robert A Copeland
May 7, 2008·Bioorganic & Medicinal Chemistry Letters·Christopher W am EndePeter J Tonge
Aug 1, 2007·Journal of Applied Crystallography·Airlie J McCoyRandy J Read

❮ Previous
Next ❯

Citations

Dec 19, 2009·The Journal of Biological Chemistry·Carl A MachuttaPeter J Tonge
Sep 8, 2009·The Journal of Antimicrobial Chemotherapy·Kathleen EnglandRichard A Slayden
Mar 12, 2011·The Journal of Antimicrobial Chemotherapy·Nina LiuPeter J Tonge
Nov 4, 2010·Acta Crystallographica. Section F, Structural Biology and Crystallization Communications·Shahila MehboobMichael E Johnson
May 17, 2014·PLoS Computational Biology·Lei XiePhilip E Bourne
Oct 25, 2011·Annual Review of Pharmacology and Toxicology·Lei XiePhilip E Bourne
Nov 11, 2014·Journal of Enzyme Inhibition and Medicinal Chemistry·Ondrej HolasMartin Dolezal
Dec 19, 2015·Nature Reviews. Drug Discovery·Robert A Copeland
Jul 23, 2011·Drug Discovery Today·Sara NúñezChris G Kruse
Jan 11, 2014·Protein Science : a Publication of the Protein Society·Ling JiangYuhui Dong
Sep 26, 2015·Neuro-oncology·Victor A LevinRussell C Petter
Sep 14, 2014·European Journal of Medicinal Chemistry·Hui WangPeter J Tonge
Jun 10, 2011·Expert Opinion on Therapeutic Patents·Xiaoyun LuQidong You
Apr 18, 2015·Biochimica Et Biophysica Acta·Roland G HeymGeorg C Terstappen
Mar 19, 2015·Bioorganic & Medicinal Chemistry Letters·Kevin P CusackAnil Vasudevan
Dec 28, 2010·Journal of Molecular Biology·Kook-Han KimEunice Eunkyeong Kim
Oct 7, 2014·Bioorganic & Medicinal Chemistry·Lorillee C TallorinMichael D Burkart
May 10, 2016·Journal of Chemical Theory and Computation·Ivan TeoTony Lelièvre
Oct 3, 2012·Acta Crystallographica. Section F, Structural Biology and Crystallization Communications·José M OteroMark J van Raaij
Nov 5, 2016·Expert Opinion on Drug Discovery·Rumin Zhang, Kenny Wong
Jun 24, 2017·ACS Chemical Neuroscience·Peter J Tonge
Aug 12, 2020·Antimicrobial Agents and Chemotherapy·Orville A PembertonYu Chen

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.