Growth medium-dependent antimicrobial activity of early stage MEP pathway inhibitors

PloS One
Sara SandersCaren L Freel Meyers

Abstract

The in vivo microenvironment of bacterial pathogens is often characterized by nutrient limitation. Consequently, conventional rich in vitro culture conditions used widely to evaluate antibacterial agents are often poorly predictive of in vivo activity, especially for agents targeting metabolic pathways. In one such pathway, the methylerythritol phosphate (MEP) pathway, which is essential for production of isoprenoids in bacterial pathogens, relatively little is known about the influence of growth environment on antibacterial properties of inhibitors targeting enzymes in this pathway. The early steps of the MEP pathway are catalyzed by 1-deoxy-d-xylulose 5-phosphate (DXP) synthase and reductoisomerase (IspC). The in vitro antibacterial efficacy of the DXP synthase inhibitor butylacetylphosphonate (BAP) was recently reported to be strongly dependent upon growth medium, with high potency observed under nutrient limitation and exceedingly weak activity in nutrient-rich conditions. In contrast, the well-known IspC inhibitor fosmidomycin has potent antibacterial activity in nutrient-rich conditions, but to date, its efficacy had not been explored under more relevant nutrient-limited conditions. The goal of this work was to thoroughly...Continue Reading

References

Mar 1, 1983·Diagnostic Microbiology and Infectious Disease·J A Washington
Apr 27, 1999·Microbiology·S Hernández-AllésV J Benedí
Jun 26, 1999·Archives of Microbiology·T P BegleyJ Xi
May 18, 2001·FEMS Microbiology Letters·W AchouakJ M Pagès
Oct 2, 2003·Bioscience, Biotechnology, and Biochemistry·Yoshiko SakamotoMakari Yamasaki
May 7, 2008·Biometals : an International Journal on the Role of Metal Ions in Biology, Biochemistry, and Medicine·Andrew T KoppischChristy E Ruggiero
Jun 19, 2008·Antimicrobial Agents and Chemotherapy·Olga DanilchankaMichael Niederweis
Nov 11, 2008·Nature Reviews. Microbiology·Jean-Marie PagèsMathias Winterhalter
Dec 23, 2008·Biochimica Et Biophysica Acta·Anne H Delcour
Apr 8, 2009·Annual Review of Biochemistry·Christopher T JurgensonSteven E Ealick
Jul 10, 2010·Current Topics in Medicinal Chemistry·Andrew J WiemerDavid F Wiemer
Dec 15, 2010·MBio·Alexandra GrubmanRichard L Ferrero
Jan 15, 2011·International Journal of Biological Sciences·Qinglin DuJianping Xie
Jul 20, 2011·Biochimica Et Biophysica Acta·Tathagata MukherjeeTadhg P Begley
Sep 1, 2011·The Journal of Biological Chemistry·Leighanne A BrammerCaren Freel Meyers
Oct 26, 2011·Bioorganic & Medicinal Chemistry Letters·Eugene UhCynthia S Dowd
Apr 3, 2012·Microbiology·Sinéad HeustonColin Hill
Oct 5, 2012·Clinical Microbiology Reviews·Lucía Fernández, Robert E W Hancock
Dec 4, 2012·Structure·Brigitte K Ziervogel, Benoît Roux
Jul 5, 2013·Nature·James E GalaganGary K Schoolnik
Jul 5, 2013·Chembiochem : a European Journal of Chemical Biology·Francine MorrisCaren L Freel Meyers

❮ Previous
Next ❯

Citations

Jan 8, 2021·ACS Applied Materials & Interfaces·Jolien BreukersJeroen Lammertyn

❮ Previous
Next ❯

Methods Mentioned

BETA
NMR

Software Mentioned

Agilent Masshunter Quantitative Analysis

Related Concepts

Related Feeds

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.