Genetik und Regulation des Staphylococcus aureus Small Colony Variant-Phänotyps

• Applicant: Professor Dr. Georg Peters, since 4/2009 (†)
• Subject Area: Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: from 2006 to 2011
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 21277563

• Final Report Year: 2011

Final Report Abstract

Small-colony variants (SCVs) represent a distinct phenotype found in staphylococci and other bacterial species. In contrast to the normal phenotype, SCVs are characterized by changes in their metabolism and physiology allowing an adaption onto an intracellular lifestyle. Of note, SCVs have been associated with chronic and relapsing infections. Within the project, all known hemin and menadione operons were sequenced applying isogenic Staphylococcus aureus strain pairs consisting of hemin-auxotrophic and menadione-auxotrophic SCVs and gentamicin-induced SCVs and their respective parental wild-type strains. While all hemin-auxotrophic SCVs did not show any differences within the sequenced regions compared to their wild-types, menadione-auxotrophic SCVs were found to contain mutations in the naphthoate synthase-encoding gene (menB), which explains the genetic basis of menadione-auxotrophic SCVs. Transcription analyses revealed a changed metabolism of hemB-knock out- und menD-knock out mutants characterized by defects of the electron transport chain. Even applying strict aerobic atmospheric conditions, metabolism of both mutants switched into an anaerobic metabolism with up-regulation of enzymes involved in glycolytic and fermentative pathways whereas the tricarboxylic acid cycle has been switched off.

Publications

• Nat Rev Microbiol. 2006 Apr; 4 (4):295-305. “Small colony variants: a pathogenic form of bacteria that facilitates persistent and recurrent infections”
  Proctor RA, von Eiff C, Kahl BC, Becker K, McNamara P, Herrmann M, Peters G
  
• „Reporter metabolite analysis of transcriptional profiles of a Staphylococcus aureus strain with normal phenotype and its isogenic hemB mutant displaying the small-colony-variant phenotype“. J Bacteriol. 2006 Nov;188 (22):7765-77
  Seggewiss J, Becker K, Kotte O, Eisenacher M, Yazdi MR, Fischer A, McNamara P, Al Laham N, Proctor R, Peters G, Heinemann M, von Eiff C.
  
• A site-directed Staphylococcus epidermidis hemB mutant displays the small colony variant phenotype and expresses larger amounts of polysaccharide intercellular adhesin. European BioPerspectives, Cologne, 30. Mai – 01. Juni 2007, LMP13 in: European BioPerspectives 2007
  Al Laham, N., H. Rohde, G. Sander, A. Fischer, M. Hussain, C. Heilmann, D. Mack, R. Proctor, G. Peters, K. Becker, C. von Eiff
  
• Biofilm formation of a Staphylococcus epidermidis hemB mutant displaying the SCV phenotype. Association for General and Applied Microbiology (VAAM), Osnabrück, 01. - 04. April 2007, PN008 in: Sonderausgabe BIOspektrum, 2007, 167
  Al Laham, N., H. Rohde, G. Sander, A. Fischer, M. Hussain, C. Heilmann, D. Mack, R. Proctor, G. Peters, K. Becker, C. von Eiff
  
• Characterization of a Staphylococcus aureus double mutant defective in hemin biosynthesis and in the global redox sensing regulator (Rex). DGHM Göttingen 2007. IJMM 297 (43): 107
  Sander, G., S. Strompen, A. Fischer, J. Seggewiß, K. Becker, P. McNamara, G. Peters,R.A. Proctor, C. von Eiff
  
• Mutations may be involved in the formation of Menadioneauxotrophic small-colony variants (SCVs) of Staphylococcus aureus recovered from clinical speciems. DGHM Göttingen 2007. IJMM 297 (43): 108
  Strompen, S., T. Cordes, G. Sander, A. Fischer, J. Seggewiß, R. A. Proctor, G. Peters, K. Becker, C. von Eiff
  
• Sequence analysis of clinical menadione- and hemin-auxotrophic small-colony variants (SCVs) of Staphylococcus aureus and their isogenic parent strains. 3rd European Conference on Prokaryotic Genomes, ProkaGen 2007, 07. – 10. Oktober 2007
  Strompen, S., T. Cordes, G. Sander, A. Fischer, J. Seggewiß, R. A. Proctor, G. Peters, K. Becker, C. von Eiff
  
• „Augmented expression of polysaccharide intercellular adhesin in a defined Staphylococcus epidermidis mutant with small colony variant phenotype“. 2007, J. Bacteriol. 189 (12):4494-501
  Al Laham N., H. Rohde, G. Sander, A. Fischer, M. Hussain, C. Heilmann, D. Mack, R. Proctor, G. Peters, K. Becker, C. von Eiff
  
• Characterization and functional investigations of a Staphylococcus aureus mutant which is deficient in both hemin biosynthesis and the global redox sensing regulator (Rex). ISSSI Cairns 2008
  Sander, G., S. Strompen, K. Becker, A. Fischer, J. Seggewiß, G. Peters, R. A. Proctor, C. von Eiff
  
• Characterization of a global redox-sensing regulator mutant of Staphylococcus aureus by a transcriptomic approach. DGHM Dresden 2008. IJMM 298 (45): 69
  Seggewiß, J., G. Sander, R. A. Proctor, G. Peters, K. Becker, C. von Eiff
  
• Impact of the Staphylococcus aureus global redox-sensing regulator on the smallcolony-variant phenotype. DGHM Dresden 2008. IJMM 298 (45): 68
  Sander, G., S. Strompen, A. Fischer, J. Seggewiß, R. A. Proctor, G. Peters, K. Becker, C. von Eiff
  
• Int J Antimicrob Agents. 2008 Jun;31 (6):507- 10. „Staphylococcus aureus small colony variants: a challenge to microbiologists and clinicians“
  von Eiff C
  
• Transcriptomic analysis of a Staphylococcus aureus mutant deficient for the global redox sensing regulator Rex. ISSSI Cairns 2008
  Seggewiß, J., G. Sander, R. A. Proctor, G. Peters, K. Becker, C. von Eiff
  
• “A defect in menadione biosynthesis induces global changes in gene expression in Staphylococcus aureus”. J Bacteriol. 2008 Oct;190 (19):6351-64
  Kohler C, von Eiff C, Liebeke M, McNamara PJ, Lalk M, Proctor RA, Hecker M, Engelmann S
  
• „Identification of the genetic basis for clinical menadione-auxotrophic small-colony variant isolates of Staphylococcus aureus“. Antimicrobial Agents and Chemotherapy. 2008. 52 (11): 4017-4022
  Lannergard, J., von Eiff, C., Sander, G., Cordes, T., Seggewiß, J., Peters, G., Proctor, R. A., Becker, K., Hughes, D.
  
• Reduced pathogenicity of a Staphylococcus aureus rex mutant. DGHM Göttingen, 2009
  Sander, G. A. Uekötter, J. Seggewiß, A. Klingele, P. McNamara, S. Strompen, N. Al Laham, R. Proctor, K. Becker, G. Peters, C von Eiff
  
• The global redox sensing regulator Rex: Transcriptomic analysis of a Staphylococcus aureus mutant. VAAM Bochum 2009
  Seggewiß, J., G. Sander, R. A. Proctor, G. Peters, K. Becker C. von Eiff
  
• Transcriptomic analysis of a Staphylococcus aureus Rex mutant. Prokagen Göttingen 2009
  Seggewiß, J., G. Sander, R. A. Proctor, G. Peters, K. Becker, C. von Eiff
  
• „Identification of differentially expressed small non-proteincoding RNAs in Staphylococcus aureus displaying both the normal and the small-colony variant phenotype“. J Mol Med. 2010 Jun; 88 (6):565-75
  Abu-Qatouseh LF, Chinni SV, Seggewiss J, Proctor RA, Brosius J, Rozhdestvensky TS, Peters G, von Eiff C, Becker K