Novel inhibitors of Chlamydia trachomatis virulence

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Nunez-Otero, Carlos,1992-Umeå universitet,Klinisk bakteriologi (author)

Novel inhibitors of Chlamydia trachomatis virulence

BookEnglish2020

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Umeå :Umeå University,2020
48 s.
electronicrdacarrier

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LIBRIS-ID:oai:DiVA.org:umu-174666
ISBN:9789178553402
ISBN:9789178553396
https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-174666URI

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Language:English
Summary in:English

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SwePubSwePub

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Subject category:vet swepub-contenttype
Subject category:dok swepub-publicationtype

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Umeå University medical dissertations,0346-6612 ;2092

Notes

Additional appendix only available in printed version, as it contains specific methods that we want to publish in the future.
Chlamydia trachomatis is an obligate intracellular bacterium that infects over 100 million people globally every year. Chlamydia infections can be persistent, cause infertility and blindness, adding an economical burden in the healthcare systems. Moreover, Chlamydia infections are treated with broad-spectrum antibiotics that contribute to the selection of antibiotic resistant bacteria in the commensal flora. For this reason, novel compounds with specificity against C. trachomatis would be important for treatment of Chlamydia infections.We have developed a new class of substituted 2-pyridone amides that inhibited development of C. trachomatis. While bacterial growth was only affected to a limited extent, the produced progeny bacteria had impaired capacity to infect new cells. The compounds presented no toxicity in human or mouse cell lines and they did not inhibit growth of bacteria from the normal flora. Structure activity relationship (SAR) development of 2-pyridones lead to compounds with effect at nanomolar concentrations. Further modifications of the C3 part of the molecules resulted in isostere compounds with even a higher potency. By exploring the C8 position, we observed that methylsulfonamide substituents improved the pharmacokinetic properties and enabled oral uptake in mice. This discovery opens the door for oral treatment.Among 2-pyridone amides, KSK213 was one of the most potent and we investigated the mode of action on the life cycle of C. trachomatis. KSK213 reduced transcription by the end of the developmental cycle and upon infection of new host cells. Mutations in RNA helicase and RNAse III genes, involved in transcription, mediated resistance to KSK213. It also attenuated the infectivity in a mouse vaginal infection model. To further explore the molecular target for 2-pyridone amides in Chlamydia, we used a custom synthesized probe for affinity chromatography approaches.Here we show that 2-pyridones are potent non-toxic inhibitors of C. trachomatis that can be chemically modified to increase potency and enable oral bioavailability. These molecules have the potential to treat and prevent Chlamydia infections without affecting the normal flora.

Subject headings and genre

MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Infektionsmedicin hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Infectious Medicine hsv//eng
MEDICIN OCH HÄLSOVETENSKAP Medicinsk bioteknologi Medicinsk bioteknologi hsv//swe
MEDICAL AND HEALTH SCIENCES Medical Biotechnology Medical Biotechnology hsv//eng
MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Läkemedelskemi hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Medicinal Chemistry hsv//eng
MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Cell- och molekylärbiologi hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Cell and Molecular Biology hsv//eng
Chlamydia trachomatis
2-pyridone
small molecules
KSK213
Structure-Activity Relationships (SAR)
antibiotic resistance
target identification
transcription
RNA
progeny
infectivity

Added entries (persons, corporate bodies, meetings, titles ...)

Gylfe, Åsa,PhD, MD,1972-Umeå universitet,Institutionen för molekylärbiologi (Medicinska fakulteten),Institutionen för klinisk mikrobiologi,Molekylär Infektionsmedicin, Sverige (MIMS)(Swepub:umu)asagye91 (thesis advisor)
Bergström, Sven,ProfessorUmeå universitet,Institutionen för molekylärbiologi (Medicinska fakulteten)(Swepub:umu)svbe0001 (thesis advisor)
Almqvist, Fredrik,ProfessorUmeå universitet,Kemiska institutionen,Umeå Centre for Microbial Research (UCMR),Molekylär Infektionsmedicin, Sverige (MIMS)(Swepub:umu)fral0001 (thesis advisor)
Johansson, Jörgen,ProfessorUmeå universitet,Molekylär Infektionsmedicin, Sverige (MIMS),Umeå Centre for Microbial Research (UCMR),Institutionen för molekylärbiologi (Medicinska fakulteten)(Swepub:umu)jojo0001 (thesis advisor)
Bavoil, Patrik,ProfessorDepartment of Microbial Pathogenesis, University of Maryland School of Dentistry, Baltimore, USA (opponent)
Umeå universitetKlinisk bakteriologi (creator_code:org_t)

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