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

Engel, Hans Jürg; Mika, Moana; Denapaite, Dalia; Hakenbeck, Regine; Mühlemann, Kathrin; Heller, Manfred; Hathaway, Lucy Jane; Hilty, Markus (2014). A low affinity penicillin-binding protein 2x is required for heteroresistance in Streptococcus pneumoniae. Antimicrobial agents and chemotherapy, 58(7), pp. 3934-3941. American Society for Microbiology 10.1128/AAC.02547-14

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Heteroresistance to penicillin in Streptococcus pneumoniae is the ability of subpopulations to grow at a higher antibiotic concentration than expected from the minimal inhibitory concentration (MIC). This may render conventional resistance testing unreliable and lead to therapeutic failure. We investigated the role of the primary β-lactam resistance determinants, penicillin binding proteins PBP2b and PBP2x and secondary resistance determinant PBP1a in heteroresistance to penicillin. Transformants containing PBP genes from heteroresistant strain Spain(23F)2349 in non-heteroresistant strain R6 background were tested for heteroresistance by population analysis profiling (PAP). We found that pbp2x, but not pbp2b or pbp1a alone, conferred heteroresistance to R6. However, a change of pbp2x expression is not observed and therefore expression does not correlate with an increased proportion of resistant subpopulations. Additional ciaR disruption mutants which have been described to mediate PBP-independent β-lactam resistance revealed no heteroresistant phenotype by PAP.We also showed, that the highly resistant subpopulations (HOM*) of transformants containing low affinity pbp2x undergo an increase in resistance upon selection on penicillin plates which partially reverts after passaging on selection-free medium. Shotgun proteomic analysis showed an upregulation of phosphate ABC transporter subunit proteins pstS, phoU, pstB and pstC in these highly resistant subpopulations.In conclusion, the presence of low affinity pbp2x enables certain pneumococcal colonies to survive in the presence of beta lactams. Upregulation of phosphate ABC transporter genes may represent a reversible adaption to antibiotic stress.

Item Type:

Journal Article (Original Article)


04 Faculty of Medicine > Service Sector > Institute for Infectious Diseases > Research
04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Infectiology
04 Faculty of Medicine > Service Sector > Institute for Infectious Diseases
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DCR Services > Core Facility Massenspektrometrie- und Proteomics-Labor

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Engel, Hans Jürg, Mika, Moana, Mühlemann, Kathrin, Heller, Manfred, Hathaway, Lucy Jane, Hilty, Markus


600 Technology > 610 Medicine & health
500 Science > 570 Life sciences; biology




American Society for Microbiology




Annelies Luginbühl

Date Deposited:

10 Oct 2014 11:08

Last Modified:

05 Dec 2022 14:34

Publisher DOI:


PubMed ID:






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