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A low-affinity penicillin-binding protein 2x variant is required for heteroresistance in Streptococcus pneumoniae

Hansjürg Engel1, Moana Mika1, Dalia Denapaite2

  • 1Institute for Infectious Diseases, Faculty of Medicine, University of Bern, Bern, Switzerland Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.

Antimicrobial Agents and Chemotherapy
|April 30, 2014
PubMed

Insights

Penicillin heteroresistance in Streptococcus pneumoniae is linked to the penicillin-binding protein 2x (pbp2x) gene. Low-affinity pbp2x allows some pneumococcal cells to survive higher antibiotic levels, with phosphate transporter gene upregulation potentially aiding adaptation.

Area of Science:

  • Microbiology
  • Molecular Biology
  • Antibiotic Resistance

Background:

  • Heteroresistance to penicillin in Streptococcus pneumoniae poses a challenge to conventional antibiotic susceptibility testing and can lead to treatment failure.
  • Understanding the genetic basis of heteroresistance is crucial for developing effective therapeutic strategies against pneumococcal infections.

Purpose of the Study:

  • To investigate the roles of primary (PBP2b, PBP2x) and secondary (PBP1a) beta-lactam resistance determinants in penicillin heteroresistance in Streptococcus pneumoniae.
  • To explore the contribution of the CiaRH system to beta-lactam resistance and heteroresistance.
  • To identify molecular mechanisms associated with highly resistant subpopulations.

Main Methods:

  • Population analysis profiling (PAP) was used to assess heteroresistance in transformant strains.
  • Genetic manipulation involved introducing specific penicillin-binding protein (PBP) genes into a non-heteroresistant background.
  • Shotgun proteomic analysis was employed to investigate protein expression changes in highly resistant subpopulations.

Main Results:

  • The pbp2x gene alone, not pbp2b or pbp1a, conferred heteroresistance to the R6 strain.
  • Changes in pbp2x expression levels did not correlate with the proportion of resistant subpopulations.
  • Disruption of the CiaRH system did not result in a heteroresistant phenotype.
  • Highly resistant subpopulations (HOM*) with low-affinity pbp2x showed increased resistance upon penicillin selection, which partially reverted without selection.
  • Proteomic analysis revealed upregulation of phosphate ABC transporter subunit proteins (pstS, phoU, pstB, pstC) in HOM* subpopulations.

Conclusions:

  • The presence of low-affinity pbp2x is sufficient to enable survival of certain Streptococcus pneumoniae subpopulations in the presence of beta-lactams.
  • Upregulation of phosphate ABC transporter genes represents a potential reversible adaptive mechanism to antibiotic stress in pneumococci.

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