Tricarboxylic acid cycle-dependent attenuation of Staphylococcus aureus in vivo virulence by selective inhibition of amino acid transport.
Staphylococci are the leading causes of endovascular infections worldwide. Commonly, these infections involve the formation of biofilms on the surface of biomaterials. Biofilms are a complex aggregation of bacteria commonly encapsulated by an adhesive exopolysaccharide matrix. In staphylococci, this exopolysaccharide matrix is composed of polysaccharide intercellular adhesin (PIA). PIA is synthesized when the tricarboxylic acid (TCA) cycle is repressed. The inverse correlation between PIA synthesis and TCA cycle activity led us to hypothesize that increasing TCA cycle activity would decrease PIA synthesis and biofilm formation and reduce virulence in a rabbit catheter-induced model of biofilm infection. TCA cycle activity can be induced by preventing staphylococci from exogenously acquiring a TCA cycle-derived amino acid necessary for growth. To determine if TCA cycle induction would decrease PIA synthesis in Staphylococcus aureus, the glutamine permease gene (glnP) was inactivated and TCA cycle activity, PIA accumulation, biofilm forming ability, and virulence in an experimental catheter-induced endovascular biofilm (endocarditis) model were determined. Inactivation of this major glutamine transporter increased TCA cycle activity, transiently decreased PIA synthesis, and significantly reduced in vivo virulence in the endocarditis model in terms of achievable bacterial densities in biofilm-associated cardiac vegetations, kidneys, and spleen. These data confirm the close linkage of TCA cycle activity and virulence factor production and establish that this metabolic linkage can be manipulated to alter infectious outcomes.
Zhu
Yefei
Y
Department of Veterinary and Biomedical Sciences, University of Nebraska, 155 VBS, Fair St. and East Campus Loop, Lincoln, NE 68583-0905, USA.
Xiong
Yan Q
YQ
Sadykov
Marat R
MR
Fey
Paul D
PD
Lei
Mei G
MG
Lee
Chia Y
CY
Bayer
Arnold S
AS
Somerville
Greg A
GA
D026923:Amino Acid Transport Systems, Basic / Q000037:antagonists & inhibitors* / Q000235:genetics; D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D018441:Biofilms / Q000254:growth & development*; D055499:Catheter-Related Infections / Q000382:microbiology; D002952:Citric Acid Cycle; D015169:Colony Count, Microbial; D004195:Disease Models, Animal; D004697:Endocarditis, Bacterial / Q000382:microbiology; D004699:Endocardium / Q000382:microbiology; D005260:Female; D017353:Gene Deletion; D006801:Humans; D007668:Kidney / Q000382:microbiology; D011135:Polysaccharides, Bacterial / Q000096:biosynthesis*; D011817:Rabbits; D013154:Spleen / Q000382:microbiology; D013203:Staphylococcal Infections / Q000382:microbiology; D013211:Staphylococcus aureus / Q000378:metabolism / Q000472:pathogenicity*; D014774:Virulence; D037521:Virulence Factors / Q000096:biosynthesis*
D026923:Amino Acid Transport Systems, Basic; D000596:Amino Acids; D011135:Polysaccharides, Bacterial; D037521:Virulence Factors; C113579:polysaccharide intercellular adhesin; C051432:glutamine permease