The Design, Synthesis, and Characterizations of Spore Germination Inhibitors Effective against an Epidemic Strain of Clostridium difficile

Journal of Medicinal Chemistry
Shiv K SharmaSteven M Firestine

Abstract

Clostridium difficile infections (CDI), particularly those caused by the BI/NAP1/027 epidemic strains, are challenging to treat. One method to address this disease is to prevent the development of CDI by inhibiting the germination of C. difficile spores. Previous studies have identified cholic amide m-sulfonic acid, CamSA, as an inhibitor of spore germination. However, CamSA is inactive against the hypervirulent strain R20291. To circumvent this problem, a series of cholic acid amides were synthesized and tested against R20291. The best compound in the series was the simple phenyl amide analogue which possessed an IC50 value of 1.8 μM, more than 225 times as potent as the natural germination inhibitor, chenodeoxycholate. This is the most potent inhibitor of C. difficile spore germination described to date. QSAR and molecular modeling analysis demonstrated that increases in hydrophobicity and decreases in partial charge or polar surface area were correlated with increases in potency.

References

Sep 29, 1976·Journal of the American Chemical Society·E J CoreyM Shibasaki
Sep 1, 2000·Journal of Medicinal Chemistry·R V FishleighS C Young
Oct 18, 2000·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·G CrucianiW Guba
Jan 6, 2001·Journal of Molecular Graphics & Modelling·P Labute
Jun 14, 2002·Journal of Medicinal Chemistry·Gabriele CrucianiRaimund Mannhold
Dec 20, 2002·Angewandte Chemie·Louis A CarpinoMichael Bienert
Jan 28, 2003·Drug Discovery Today·Chandra L Tucker
May 10, 2007·Postgraduate Medical Journal·Barry Cookson
Jan 5, 2008·Nature Clinical Practice. Gastroenterology & Hepatology·Lynne V McFarland
Feb 5, 2008·Journal of Bacteriology·Joseph A Sorg, Abraham L Sonenshein
Oct 31, 2008·The New England Journal of Medicine·Ciarán P Kelly, J Thomas LaMont
Dec 9, 2008·Journal of Bacteriology·Joseph A Sorg, Abraham L Sonenshein
Feb 13, 2010·Molecular Biotechnology·W Frank An, Nicola Tolliday
Jun 22, 2010·Journal of Bacteriology·Norma RamirezErnesto Abel-Santos
Jul 14, 2010·Analytical and Bioanalytical Chemistry·Elisa MicheliniAldo Roda
Oct 26, 2010·Journal of Bacteriology·Amber HowertonErnesto Abel-Santos
Aug 21, 2012·Journal of Bacteriology·Xuan Yi ButzinPeter Setlow
Feb 20, 2013·The Journal of Infectious Diseases·Amber HowertonErnesto Abel-Santos
Mar 7, 2013·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·A Sarah WalkerUNKNOWN Infections in Oxfordshire Research Database
Sep 12, 2013·PloS One·Amber HowertonErnesto Abel-Santos
Dec 20, 2013·Journal of Medicinal Chemistry·Artem CherkasovAlexander Tropsha
May 13, 2014·Trends in Microbiology·Daniel Paredes-SabjaJoseph A Sorg
Dec 24, 2014·Infection and Immunity·Mark J KoenigsknechtVincent B Young
Apr 16, 2015·The New England Journal of Medicine·Daniel A Leffler, J Thomas Lamont
Jan 9, 2016·The Canadian Journal of Infectious Diseases & Medical Microbiology = Journal Canadien Des Maladies Infectieuses Et De La Microbiologie Médicale·George G ZhanelJames A Karlowsky
Aug 31, 2016·Nature Reviews. Microbiology·Michael C AbtEric G Pamer
Jan 15, 2017·Gut·Giovanni CammarotaUNKNOWN European FMT Working Group
Apr 11, 2017·ACS Applied Materials & Interfaces·Margarida M FernandesTzanko Tzanov
May 11, 2017·Nature·Michelle F RichterPaul J Hergenrother
Jul 13, 2017·Annual Review of Microbiology·Peter SetlowYong-Qing Li
Jul 14, 2017·PLoS Pathogens·Travis J KochanPhilip C Hanna
Oct 20, 2017·FEMS Microbiology Reviews·Ramyavardhanee Chandrasekaran, D Borden Lacy
Feb 27, 2018·Gastroenterology Report·Roy J Hopkins, Robert B Wilson
Mar 8, 2018·Transplant Infectious Disease : an Official Journal of the Transplantation Society·Cynthia T NguyenJonathan Hand
Mar 22, 2018·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·L Clifford McDonaldMark H Wilcox

❮ 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.

Related Papers

International Journal of Infectious Diseases : IJID : Official Publication of the International Society for Infectious Diseases
Konstantinos Z VardakasMatthew E Falagas
Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America
Louis ValiquetteGérard Schmutz
The New England Journal of Medicine
M H Wilcox, J Freeman
© 2022 Meta ULC. All rights reserved