A 2-pyridone amide inhibitor of transcriptional activity in Chlamydia trachomatis

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Núñez-Otero, CarlosUmeå universitet,Institutionen för klinisk mikrobiologi (author)

A 2-pyridone amide inhibitor of transcriptional activity in Chlamydia trachomatis

Article/chapterEnglish2021

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American Society for Microbiology,2021
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LIBRIS-ID:oai:DiVA.org:umu-174665
https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-174665URI
https://doi.org/10.1128/AAC.01826-20DOI

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Language:English
Summary in:English

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Subject category:art swepub-publicationtype

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Originally included in thesis in manuscript form.
Chlamydia trachomatis is a strict intracellular bacterium that causes sexually transmitted infections and eye infections that can lead to lifelong sequelae. Treatment options are limited to broad-spectrum antibiotics that disturb the commensal flora and contribute to selection of antibiotic-resistant bacteria. Hence, development of novel drugs that specifically target C. trachomatis would be beneficial. 2-Pyridone amides are potent and specific inhibitors of Chlamydia infectivity. The first-generation compound KSK120 inhibits the developmental cycle of Chlamydia, resulting in reduced infectivity of progeny bacteria. Here, we show that the improved, highly potent second-generation 2-pyridone amide KSK213 allowed normal growth and development of C. trachomatis, and the effect was only observable upon reinfection of new cells. Progeny elementary bodies (EBs) produced in the presence of KSK213 were unable to activate transcription of essential genes in early development and did not differentiate into the replicative form, the reticulate body (RB). The effect was specific to C. trachomatis since KSK213 was inactive in the closely related animal pathogen Chlamydia muridarum and in Chlamydia caviae. The molecular target of KSK213 may thus be different in C. trachomatis or nonessential in C. muridarum and C. caviae. Resistance to KSK213 was mediated by a combination of amino acid substitutions in both DEAD/DEAH RNA helicase and RNase III, which may indicate inhibition of the transcriptional machinery as the mode of action. 2-Pyridone amides provide a novel antibacterial strategy and starting points for development of highly specific drugs for C. trachomatis infections.

Subject headings and genre

MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Infektionsmedicin hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Infectious Medicine hsv//eng
Chlamydia trachomatis
antibacterial agents
intracellular bacteria
mode of action
virulence inhibitors

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Bahnan, WaelUmeå universitet,Institutionen för molekylärbiologi (Medicinska fakulteten)(Swepub:umu)waba0006 (author)
Vielfort, KatarinaUmeå universitet,Institutionen för molekylärbiologi (Medicinska fakulteten)(Swepub:umu)kavi0052 (author)
Silver, JimUmeå universitet,Institutionen för molekylärbiologi (Medicinska fakulteten)(Swepub:umu)jiisir01 (author)
Singh, PardeepUmeå universitet,Kemiska institutionen(Swepub:umu)pasi0012 (author)
Elbir, HaithamUmeå universitet,Institutionen för molekylärbiologi (Medicinska fakulteten)(Swepub:umu)hael0020 (author)
Almqvist, FredrikUmeå universitet,Kemiska institutionen(Swepub:umu)fral0001 (author)
Bergström, SvenUmeå universitet,Institutionen för molekylärbiologi (Medicinska fakulteten)(Swepub:umu)svbe0001 (author)
Gylfe, Åsa,1972-Umeå universitet,Institutionen för klinisk mikrobiologi(Swepub:umu)asagye91 (author)
Umeå universitetInstitutionen för klinisk mikrobiologi (creator_code:org_t)

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In:Antimicrobial Agents and Chemotherapy: American Society for Microbiology65:50066-48041098-6596

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By the author/editor: Núñez-Otero, Car ...; Bahnan, Wael; Vielfort, Katari ...; Silver, Jim; Singh, Pardeep; Elbir, Haitham; show more...; Almqvist, Fredri ...; Bergström, Sven; Gylfe, Åsa, 1972 ...; show less...

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