Abstract (Expand)
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 …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.
Authors: Philip Eisenberg, Leon Albert, Jonathan Teuffel, Eric Zitzow, Claudia Michaelis, Jane Jarick, Clemens Sehlke, Lisa Große, Nicole Bader, Ariane Nunes-Alves, Bernd Kreikemeyer, Hermann Schindelin, Rebecca C. Wade, Tomas Fiedler
Date Published: 15th Feb 2022
Publication Type: Journal
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