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Improved N-phenylpyrrolamide inhibitors of DNA gyrase as antibacterial agents for high-priority bacterial strains
ID
Zidar, Nace
(
Author
),
ID
Onali, Alessia
(
Author
),
ID
Peršolja, Peter
(
Author
),
ID
Benedetto Tiz, Davide
(
Author
),
ID
Dernovšek, Jaka
(
Author
),
ID
Skok, Žiga
(
Author
),
ID
Durcik, Martina
(
Author
),
ID
Cotman, Andrej Emanuel
(
Author
),
ID
Hrast, Martina
(
Author
),
ID
Zega, Anamarija
(
Author
),
ID
Peterlin-Mašič, Lucija
(
Author
),
ID
Ilaš, Janez
(
Author
),
ID
Tomašič, Tihomir
(
Author
),
ID
Kikelj, Danijel
(
Author
), et al.
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MD5: 0871C69817F57D13F046800A9DF18B92
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https://www.sciencedirect.com/science/article/pii/S0223523424007049
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Abstract
In this work, we describe an improved series of N-phenylpyrrolamide inhibitors that exhibit potent activity against DNA gyrase and are highly effective against high-priority gram-positive bacteria. The most potent compounds show low nanomolar IC$_{50}$ values against Escherichia coli DNA gyrase, and in addition, compound 7c also inhibits E. coli topoisomerase IV in the nanomolar concentration range, making it a promising candidate for the development of potent dual inhibitors for these enzymes. All tested compounds show high selectivity towards the human isoform DNA topoisomerase IIα. Compounds 6a, 6d, 6e and 6f show MIC values between 0.031 and 0.0625 μg/mL against vancomycin-intermediate S. aureus (VISA) and Enterococcus faecalis strains. Compound 6g shows an inhibitory effect against the methicillin-resistant S. aureus strain (MRSA) with a MIC of 0.0625 μg/mL and against the E. faecalis strain with a MIC of 0.125 μg/mL. In a time-kill assay, compound 6d showed a dose-dependent bactericidal effect on the MRSA strain and achieved bactericidal activity at 8 × MIC after 8 h. The duration of the post-antibiotic effect (PAE) on the MRSA strain for compound 6d was 2 h, which corresponds to the PAE duration for ciprofloxacin. The compounds were not cytotoxic at effective concentrations, as determined in an MTS assay on the MCF-7 breast cancer cell line.
Language:
English
Keywords:
antibacterial agents
,
DNA gyrase
,
GyrB
,
inhibitor
,
N-phenylpyrrolamide
,
ParE
,
topoisomerase IV
Work type:
Article
Typology:
1.01 - Original Scientific Article
Organization:
FFA - Faculty of Pharmacy
Publication status:
Published
Publication version:
Version of Record
Year:
2024
Number of pages:
19 str.
Numbering:
Vol. 278, art. 116823
PID:
20.500.12556/RUL-161296-97649312-2105-afd9-1e19-84dcee14eee0
UDC:
615.4:54
ISSN on article:
1768-3254
DOI:
10.1016/j.ejmech.2024.116823
COBISS.SI-ID:
206357251
Publication date in RUL:
09.09.2024
Views:
33
Downloads:
31
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Record is a part of a journal
Title:
European journal of medicinal chemistry
Shortened title:
Eur. j. med. chem.
Publisher:
Elsevier
ISSN:
1768-3254
COBISS.SI-ID:
23138309
Licences
License:
CC BY-NC 4.0, Creative Commons Attribution-NonCommercial 4.0 International
Link:
http://creativecommons.org/licenses/by-nc/4.0/
Description:
A creative commons license that bans commercial use, but the users don’t have to license their derivative works on the same terms.
Secondary language
Language:
Slovenian
Keywords:
antibakterijski zaviralci
,
DNA giraze
,
GyrB
,
N-fenilpirolamid
,
ParE
,
topoizomeraza IV
,
farmacevtska kemija
Projects
Funder:
ARRS - Slovenian Research Agency
Project number:
P1-0208
Name:
Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin
Funder:
ARRS - Slovenian Research Agency
Project number:
J1-3021
Name:
Platforma, osnovana na sintetičnih biofilmih za preučevanje in razvoj novih protibiofilmskih pristopov
Funder:
ARRS - Slovenian Research Agency
Project number:
J1-3031
Name:
Razvoj novih zaviralcev bakterijskih topoizomeraz za boj proti odpornim infekcijam
Funder:
AKA - Academy of Finland
Project number:
321551
Name:
Evolving the next generation of Gram-negative antimicrobials through a synergetic approach encompassing medicinal chemistry, microbiology and nanomedicine tools / Consortium: NO-ESCAPE
Funder:
Other - Other funder or multiple funders
Funding programme:
Hungary, Ministry of Culture and Innovation, The New National Excellence Program
Funder:
Other - Other funder or multiple funders
Funding programme:
Hungary, Ministry of Culture and Innovation, National Biomedical Foundation, The National Academy of Scientist Education
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