Publikation: Zeitschriftenartikel

The non-phosphorylating glyceraldehyde-3-phosphate dehydrogenase GapN is a potential new drug target in Streptococcus pyogenes

Grunddaten
Abstract
Autoren
Einrichtung

Grunddaten

Titel	The non-phosphorylating glyceraldehyde-3-phosphate dehydrogenase GapN is a potential new drug target in Streptococcus pyogenes
Erscheinungsjahr	2022
Seiten (von – bis)	1 – 18
Band	13
Jahr	2022
Publikationsform	Elektronische Ressource
Publikationsart	Zeitschriftenartikel
Sprache	Englisch
DOI	10.3389/fmicb.2022.802427
Letzte Änderung	11.01.2023 06:02:13
Bearbeitungsstatus	durch UB Rostock abschließend validiert
Dauerhafte URL	http://purl.uni-rostock.de/fodb/pub/68944
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Abstract

The strict human pathogen Streptococcus pyogenes causes infections of varying severity, ranging from self-limiting suppurative infections to life-threatening diseases like necrotizing fasciitis or streptococcal toxic shock syndrome. Here, we show that the non-phosphorylating glyceraldehyde-3-phosphate dehydrogenase GapN is an essential enzyme for S. pyogenes. GapN converts glyceraldehyde 3-phosphate into 3-phosphoglycerate coupled to the reduction of NADP to NADPH. The knock-down of gapN by antisense peptide nucleic acids (asPNA) significantly reduces viable bacterial counts of S. pyogenes laboratory and macrolide-resistant clinical strains in vitro. As S. pyogenes lacks the oxidative part of the pentose phosphate pathway, GapN appears to be the major NADPH source for the bacterium. Accordingly, other streptococci that carry a complete pentose phosphate pathway are not prone to asPNA-based gapN knock-down. Determination of the crystal structure of the S. pyogenes GapN apo-enzyme revealed an unusual cis-peptide in proximity to the catalytic binding site. Furthermore, using a structural modeling approach, we correctly predicted competitive inhibition of S. pyogenes GapN by erythrose 4-phosphate, indicating that our structural model can be used for in silico screening of specific GapN inhibitors. In conclusion, the data provided here reveal that GapN is a potential target for antimicrobial substances that selectively kill S. pyogenes and other streptococci that lack the oxidative part of the pentose phosphate pathway.

Autoren

Eisenberg, Philip
Albert, Leon
Teuffel, Jonathan
Zitzow, Eric
Michaelis, Claudia
Jarick, Jane
Sehlke, Clemens
Große, Lisa
Bader, Nicole
Nunes-Alves, Ariane
Kreikemeyer, Bernd
Schindelin, Hermann
Wade, Rebecca C.
Fiedler, Tomas

Einrichtung

UMR/Institut für Medizinische Mikrobiologie, Virologie und Hygiene, Abteilung für Virologie und Hygiene