uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Further characterisation of the bifunctional HPPK-DHPS from Plasmodium falciparum
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
(English)Manuscript (Other academic)
Identifiers
URN: urn:nbn:se:uu:diva-93135OAI: oai:DiVA.org:uu-93135DiVA: diva2:166518
Available from: 2005-05-13 Created: 2005-05-13 Last updated: 2011-11-24
In thesis
1. Microbial Responses to Antibiotics – Stability of Resistance and Extended Potential of Targeting the Folate Synthesis
Open this publication in new window or tab >>Microbial Responses to Antibiotics – Stability of Resistance and Extended Potential of Targeting the Folate Synthesis
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Resistance to antimicrobials is an increasing problem in the world of today, and develops faster than man can counter. It is therefore of importance to study metabolic pathways in order to develop new antibiotics, but also to understand how resistance spreads and stabilizes in microbial populations.

The commensal flora could be an important factor in the spread of antimicrobial resistance, as drugs aimed at other targets also hit the harmless commensal bacteria. If stable resistance develops in such a population, it could seriously impair a later treatment with the same drug. After a treatment with the macrolide clarithromycin, resistance to this antibiotic increased markedly in the untargeted throat flora, and resistance levels did not recede until at least one year later.

Another example of stable resistance can also be seen in sulfonamide resistant Streptococcus pyogenes. Sequence determinations of the dihydropteroate synthase (dhps) gene conferring this resistance revealed a mosaic organisation implying that the it had been brought there by horizontal transfer. Molecular characterization of this gene showed that the sulfonamide resistance was due to mutations of structurally important amino acids in position 65 and 213.

The folate synthesis pathway has potential for being exploited further as a drug target. One possible new drug target is hydroxymethyl-dihydropterin pyrophosphokinase (hppk). In the malaria parasite Plasmodium falciparum this enzyme is part of a polyfunctional entity, also encoding dhps. The HPPK part can be separated from DHPS, but that the opposite is not possible. The PfHPPK has two insertions: one also present in other plasmodia, and one apparently unique to P. falciparum. Both are crucial for enzyme activity.

To further characterize HPPK, we developed a spectrophotometric activity assay and a method to measure substrate channelling of hydroxymethyl-dihydropterin diphosphate.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2005. 54 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 45
Keyword
Molecular biology, sulfonamide resistance, macrolide, commensal flora, substrate channeling, folate synthesis, Molekylärbiologi
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-5819 (URN)91-554-6268-5 (ISBN)
Public defence
2005-09-02, Room C10:301, Biomedicinskt Centrum (BMC), Uppsala, 09:15
Opponent
Supervisors
Available from: 2005-05-13 Created: 2005-05-13Bibliographically approved

Open Access in DiVA

No full text

Authority records BETA

Rosenling, ThereseSwedberg, Göte

Search in DiVA

By author/editor
Rosenling, ThereseSwedberg, Göte
By organisation
Department of Medical Biochemistry and Microbiology

Search outside of DiVA

GoogleGoogle Scholar

urn-nbn

Altmetric score

urn-nbn
Total: 483 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf