Toward new therapeutics for skin and soft tissue infections: propargyl-linked antifolates are potent inhibitors of MRSA and Streptococcus pyogenes.

PloS One
Kishore ViswanathanDennis L Wright

Abstract

Hospital- and community-acquired, complicated skin and soft tissue infections, often attributed to Staphylococcus aureus and Streptococcus pyogenes, present a significant health burden that is associated with increased health care costs and mortality. As these two species are difficult to discern on diagnosis and are associated with differential profiles of drug resistance, the development of an efficacious antibacterial agent that targets both organisms is a high priority. Herein we describe a structure-based drug development effort that has produced highly potent inhibitors of dihydrofolate reductase from both species. Optimized propargyl-linked antifolates containing a key pyridyl substituent display antibacterial activity against both methicillin-resistant S. aureus and S. pyogenes at MIC values below 0.1 µg/mL and minimal cytotoxicity against mammalian cells. Further evaluation against a panel of clinical isolates shows good efficacy against a range of important phenotypes such as hospital- and community-acquired strains as well as strains resistant to vancomycin.

References

Nov 1, 1973·The Journal of Infectious Diseases·R Then, P Angehrn
Feb 1, 1995·Antimicrobial Agents and Chemotherapy·P HuovinenO Sköld
Feb 1, 1997·The Pediatric Infectious Disease Journal·G L Darmstadt
Oct 8, 1999·The Journal of Antimicrobial Chemotherapy·R L Nichols
Nov 19, 2003·Bioorganic & Medicinal Chemistry Letters·Peter SchneiderKhalid Islam
Jul 23, 2004·Expert Opinion on Investigational Drugs·Alex J O'Neill, Ian Chopra
Dec 2, 2004·American Journal of Infection Control·UNKNOWN National Nosocomial Infections Surveillance System
Oct 19, 2005·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Dennis L StevensUNKNOWN Infectious Diseases Society of America
Dec 20, 2005·Biochemical Pharmacology·Stephen HawserKhalid Islam
Feb 1, 2006·Clinical Microbiology and Infection : the Official Publication of the European Society of Clinical Microbiology and Infectious Diseases·G C Schito
Feb 1, 2006·Clinical Microbiology and Infection : the Official Publication of the European Society of Clinical Microbiology and Infectious Diseases·M F Q Kluytmans-Vandenbergh, J A J W Kluytmans
Mar 4, 2006·Current Opinion in Infectious Diseases·Marin H Kollef, Scott T Micek
Mar 10, 2006·Clinical Microbiology and Infection : the Official Publication of the European Society of Clinical Microbiology and Infectious Diseases·P C Appelbaum
Dec 14, 2006·Acta Crystallographica. Section D, Biological Crystallography·Airlie J McCoy
Jan 17, 2008·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Richard A Proctor
Jan 26, 2008·The Journal of Antimicrobial Chemotherapy·Sandra S RichterGary V Doern
Jun 24, 2008·Journal of Medical Toxicology : Official Journal of the American College of Medical Toxicology·Danielle E Turner-Lawrence, William Kerns Ii
Apr 23, 2009·The Journal of Antimicrobial Chemotherapy·Anna A VickersAlex J O'Neill
May 14, 2009·The Annals of Pharmacotherapy·Carrie A Sincak, Justin M Schmidt
Jan 9, 2010·The Journal of Pharmacology and Experimental Therapeutics·Rosemary A NdoloJeffrey P Krise
Jul 21, 2010·Proceedings of the National Academy of Sciences of the United States of America·Kathleen M FreyAmy C Anderson
Dec 28, 2010·Toxicology in Vitro : an International Journal Published in Association with BIBRA·Sashi NadanacivaYvonne Will

❮ Previous
Next ❯

Citations

Mar 25, 2014·Expert Opinion on Therapeutic Patents·Amy C Anderson, Dennis L Wright
Jan 2, 2015·Proceedings of the National Academy of Sciences of the United States of America·Stephanie M ReeveAmy C Anderson
Feb 27, 2014·Journal of Medicinal Chemistry·Narendran G-DayanandanAmy C Anderson
Jun 23, 2015·Journal of the American Chemical Society·Santosh KeshipeddyDennis L Wright
Jul 21, 2016·ACS Medicinal Chemistry Letters·Eric ScoccheraDennis L Wright
Mar 23, 2017·Journal of Natural Products·Andrea A StierleDorota Klepacki
May 25, 2016·Biochimica Et Biophysica Acta. General Subjects·Kinga Nyíri, Beáta G Vértessy
Jul 21, 2012·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Wangda ZhouDennis L Wright
Oct 12, 2019·International Journal of Molecular Sciences·Daniel Fernández-VillaLuis Rojo
Apr 12, 2012·Antimicrobial Agents and Chemotherapy·Kathleen M FreyAmy C Anderson
Dec 2, 2021·Journal of Natural Products·Andrea A StierleNathan Gibson

❮ Previous
Next ❯

Methods Mentioned

BETA
FCS
acetylation
PCR

Software Mentioned

COOT
Phaser
Refmac5

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.