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@ARTICLE{Szal:614105,
author = {Szal, Tania and Chauhan, Shweta Singh and Lewe, Philipp and
Rachad, Fatima-Zahra and Madre, Marina and Paunina, Laura
and Witt, Susanne and Parthasarathi, Ramakrishnan and
Windshuegel, Bjoern},
title = {{E}fflux {P}ump-{B}inding
4(3-{A}minocyclobutyl){P}yrimidin-2-{A}mines {A}re
{C}olloidal {A}ggregators},
journal = {Biomolecules},
volume = {13},
number = {6},
issn = {2218-273X},
address = {Basel},
publisher = {MDPI},
reportid = {PUBDB-2024-05739},
pages = {1000},
year = {2023},
abstract = {Efflux pumps are a relevant factor in antimicrobial
resistance. In E. coli, the tripartite efflux pump
AcrAB-TolC removes a chemically diverse set of antibiotics
from the bacterium. Therefore, small molecules interfering
with efflux pump function are considered adjuvants for
improving antimicrobial therapies. Several compounds
targeting the periplasmic adapter protein AcrA and the
efflux pump AcrB have been identified to act synergistically
with different antibiotics. Among those, several
4(3-aminocyclobutyl)pyrimidin-2-amines have been shown to
bind to both proteins. In this study, we intended to
identify analogs of these substances with improved binding
affinity to AcrA using virtual screening followed by
experimental validation. While we succeeded in identifying
several compounds showing a synergistic effect with
erythromycin on E. coli, biophysical studies suggested that
4(3-aminocyclobutyl)pyrimidin-2-amines form colloidal
aggregates that do not bind specifically to AcrA. Therefore,
these substances are not suited for further development. Our
study emphasizes the importance of implementing additional
control experiments to identify aggregators among bioactive
compounds.},
cin = {CSSB-CF-PP},
ddc = {570},
cid = {I:(DE-H253)CSSB-CF-PP-20210530},
pnm = {899 - ohne Topic (POF4-899)},
pid = {G:(DE-HGF)POF4-899},
experiment = {EXP:(DE-MLZ)NOSPEC-20140101},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:37371580},
UT = {WOS:001017057600001},
doi = {10.3390/biom13061000},
url = {https://bib-pubdb1.desy.de/record/614105},
}