Inhibiting Pneumococcal Surface Antigen A (PsaA) with Small Molecules Discovered through Virtual Screening: Steps toward Validating a Potential Target for Streptococcus pneumoniae

Chemistry & Biodiversity
Ahmad J ObaidullahGlen E Kellogg

Abstract

The pneumococcal surface antigen A (PsaA) metal transporter protein provides manganese to bacterial cells. The X-ray crystal structures of PsaA, in both closed (Mn bound) and open (metal free) conformations, were explored with virtual screening to identify potential inhibitors of manganese transport. We pursued three strategies for inhibition: i) targeting a cavity close to the bound Mn to keep the metal in place; ii) targeting the metal-free Mn site to prevent metal uptake; and iii) targeting a potentially druggable allosteric site involving loops that translate between the conformations. Tiered assays were used to test the resulting 170 acquired hits: i) assay 1 tested the compounds' growth inhibition of the TIGR4 S. pneumoniae strain (ΔPsaA mutant control), yielding 80 compounds (MIC≤250 μm); ii) assay 2 tested if the addition of 20 μm Mn to inhibited cell cultures restored growth, yielding 21 compounds; and iii) assay 3 confirmed that the restored bacterial growth was Mn concentration dependent, as was the restoration of ΔPsaA growth, yielding 12 compounds with MICs of 125 μm or greater. It may be possible for a small molecule to inhibit PsaA, but we have not yet identified a compound with exemplary properties.

References

Sep 24, 1999·Thorax·J R Catterall
Nov 24, 1999·The Journal of Infectious Diseases·C J KolmanN Tuross
Oct 16, 2002·Journal of Chemical Information and Computer Sciences·Ping-an He, Jun Wang
Oct 14, 2004·Journal de gynécologie, obstétrique et biologie de la reproduction·R-C Rudigoz
Jul 31, 2007·Journal of Structural Biology·Arnaud JavelleFritz K Winkler
Aug 20, 2009·Acta Crystallographica. Section D, Biological Crystallography·Kenji OkuyamaLuigi Vitagliano
Apr 25, 2012·Protoplasma·Julie GranthamRoger Karlsson
Jun 6, 2012·Current Drug Targets·Daniel J EricssonRenato Morona
Sep 6, 2012·Journal of Chemical Information and Modeling·Lu ChenShuxing Zhang
Sep 10, 2014·Molecular BioSystems·Mahdieh Hadi, Sayed-Amir Marashi
May 2, 2015·Biometals : an International Journal on the Role of Metal Ions in Biology, Biochemistry, and Medicine·Alvin L CrumblissDennis J Thiele
Mar 24, 2016·MBio·Lance E KellerLarry S McDaniel
Jun 16, 2016·F1000Research·George A Truskey
Aug 24, 2016·Archives of Biochemistry and Biophysics·Henry Jay FormanKelvin J A Davies
Nov 14, 2016·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America

❮ Previous
Next ❯

Citations

Oct 1, 2021·Genes and Immunity·Ann-Kathrin MixChristof R Hauck

❮ 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.

Bacterial Pneumonia (ASM)

Bacterial pneumonia is a prevalent and costly infection that is a significant cause of morbidity and mortality in patients of all ages. Here is the latest research.

ApoE, Lipids & Cholesterol

Serum cholesterol, triglycerides, apolipoprotein B (APOB)-containing lipoproteins (very low-density lipoprotein (VLDL), immediate-density lipoprotein (IDL), and low-density lipoprotein (LDL), lipoprotein A (LPA)) and the total cholesterol/high-density lipoprotein (HDL) cholesterol ratio are all connected in diseases. Here is the latest research.

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.

Bacterial Pneumonia

Bacterial pneumonia is a prevalent and costly infection that is a significant cause of morbidity and mortality in patients of all ages. Here is the latest research.