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Antibacterial compounds against non-growing and intracellular bacteria

Kaldalu, Niilo ; Bērziņš, Normunds ; Berglund Fick, Stina ; Sharma, Atin ; Andersson, Naomi Charlotta ; Aedla, Jüri ; Hinnu, Mariliis ; Puhar, Andrea ; Hauryliuk, Vasili LU orcid and Tenson, Tanel (2025) In npj antimicrobials and resistance 3(1).
Abstract

Slow- and non-growing bacterial populations, along with intracellular pathogens, often evade standard antibacterial treatments and are linked to persistent and recurrent infections. This necessitates the development of therapies specifically targeting nonproliferating bacteria. To identify compounds active against non-growing uropathogenic Escherichia coli (UPEC) we performed a drug-repurposing screen of 6454 approved drugs and drug candidates. Using dilution-regrowth assays, we identified 39 compounds that either kill non-growing UPEC or delay its regrowth post-treatment. The hits include fluoroquinolones, macrolides, rifamycins, biguanide disinfectants, a pleuromutilin, and anti-cancer agents. Twenty-nine of the hits have not... (More)

Slow- and non-growing bacterial populations, along with intracellular pathogens, often evade standard antibacterial treatments and are linked to persistent and recurrent infections. This necessitates the development of therapies specifically targeting nonproliferating bacteria. To identify compounds active against non-growing uropathogenic Escherichia coli (UPEC) we performed a drug-repurposing screen of 6454 approved drugs and drug candidates. Using dilution-regrowth assays, we identified 39 compounds that either kill non-growing UPEC or delay its regrowth post-treatment. The hits include fluoroquinolones, macrolides, rifamycins, biguanide disinfectants, a pleuromutilin, and anti-cancer agents. Twenty-nine of the hits have not previously been recognized as active against non-growing bacteria. The hits were further tested against non-growing Pseudomonas aeruginosa and Staphylococcus aureus. Ten compounds - solithromycin, rifabutin, mitomycin C, and seven fluoroquinolones-have strong bactericidal activity against non-growing P. aeruginosa, killing >4 log10 of bacteria at 2.5 µM. Solithromycin, valnemulin, evofosfamide, and satraplatin are unique in their ability to selectively target non-growing bacteria, exhibiting poor efficacy against growing bacteria. Finally, 31 hit compounds inhibit the growth of intracellular Shigella flexneri in a human enterocyte infection model, indicating their ability to permeate the cytoplasm of host cells. The identified compounds hold potential for treating persistent infections, warranting further comparative studies with current standard-of-care antibiotics.

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type
Contribution to journal
publication status
published
subject
in
npj antimicrobials and resistance
volume
3
issue
1
article number
25
external identifiers
  • pmid:40216902
ISSN
2731-8745
DOI
10.1038/s44259-025-00097-0
language
English
LU publication?
yes
additional info
© 2025. The Author(s).
id
9e5f47a4-5715-4678-8daf-ccc1a3bfd195
date added to LUP
2025-04-12 13:11:44
date last changed
2025-04-14 08:46:38
@article{9e5f47a4-5715-4678-8daf-ccc1a3bfd195,
  abstract     = {{<p>Slow- and non-growing bacterial populations, along with intracellular pathogens, often evade standard antibacterial treatments and are linked to persistent and recurrent infections. This necessitates the development of therapies specifically targeting nonproliferating bacteria. To identify compounds active against non-growing uropathogenic Escherichia coli (UPEC) we performed a drug-repurposing screen of 6454 approved drugs and drug candidates. Using dilution-regrowth assays, we identified 39 compounds that either kill non-growing UPEC or delay its regrowth post-treatment. The hits include fluoroquinolones, macrolides, rifamycins, biguanide disinfectants, a pleuromutilin, and anti-cancer agents. Twenty-nine of the hits have not previously been recognized as active against non-growing bacteria. The hits were further tested against non-growing Pseudomonas aeruginosa and Staphylococcus aureus. Ten compounds - solithromycin, rifabutin, mitomycin C, and seven fluoroquinolones-have strong bactericidal activity against non-growing P. aeruginosa, killing &gt;4 log10 of bacteria at 2.5 µM. Solithromycin, valnemulin, evofosfamide, and satraplatin are unique in their ability to selectively target non-growing bacteria, exhibiting poor efficacy against growing bacteria. Finally, 31 hit compounds inhibit the growth of intracellular Shigella flexneri in a human enterocyte infection model, indicating their ability to permeate the cytoplasm of host cells. The identified compounds hold potential for treating persistent infections, warranting further comparative studies with current standard-of-care antibiotics.</p>}},
  author       = {{Kaldalu, Niilo and Bērziņš, Normunds and Berglund Fick, Stina and Sharma, Atin and Andersson, Naomi Charlotta and Aedla, Jüri and Hinnu, Mariliis and Puhar, Andrea and Hauryliuk, Vasili and Tenson, Tanel}},
  issn         = {{2731-8745}},
  language     = {{eng}},
  month        = {{04}},
  number       = {{1}},
  series       = {{npj antimicrobials and resistance}},
  title        = {{Antibacterial compounds against non-growing and intracellular bacteria}},
  url          = {{http://dx.doi.org/10.1038/s44259-025-00097-0}},
  doi          = {{10.1038/s44259-025-00097-0}},
  volume       = {{3}},
  year         = {{2025}},
}