2015
DOI: 10.1021/jm501449u
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Abstract: We report the results of an investigation of the activity of a series of amidine and bisamidine compounds against Staphylococcus aureus and Escherichia coli. The most active compounds bound to an AT-rich DNA dodecamer (CGCGAATTCGCG)2, and using DSC were found to increase the melting transition by up to 24 °C. Several compounds also inhibited undecaprenyl diphosphate synthase (UPPS) with IC50 values of 100–500 nM and we found good correlations (R2 = 0.89, S. aureus; R2 = 0.79, E. coli)) between experimental and… Show more

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Cited by 46 publications
(59 citation statements)
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“…This possibility was confirmed by the ability of one of the inhibitors of undecaprenyl pyrophosphate synthase, shown in Scheme (9), to additionally intercalate with DNA [185].…”
Section: Antibacterial Bisphosphonatesmentioning
confidence: 84%
“…This possibility was confirmed by the ability of one of the inhibitors of undecaprenyl pyrophosphate synthase, shown in Scheme (9), to additionally intercalate with DNA [185].…”
Section: Antibacterial Bisphosphonatesmentioning
confidence: 84%
“…To investigate the mechanism of UppS inhibition by clomiphene, we solved the structure of E. coli UppS (EcUppS) to 2.15-Å resolution in the presence of clomiphene. We turned to the E. coli UppS homolog, as it has been shown to have strong sequence and structural similarities with the S. aureus UppS and higher crystallization success rates than the S. aureus enzyme (26). Although our cocrystal structure is not fully resolved (refined to ∼80% occupancy with the diethylamino group omitted due to disorder) and only clearly bound to one monomer in the asymmetric unit (in keeping with previous UppS/inhibitor complexes; Materials and Methods), density consistent with clomiphene is observed at the hydrophobic center of the protein in the channel that links binding sites 1, 2, and 3 with binding site 4 ( Fig.…”
Section: Sensitization Of Mrsa To β-Lactam Antibiotics Point To a Clomentioning
confidence: 99%
“…2), with EC 50 s of 3.2, 3.4, and 4.5 M, respectively. These active compounds were symmetric cyclic forms of diamidines, and it was reported previously that these compounds are active against some bacteria and parasites through various killing mechanisms (37,41). Since these compounds are known to bind to AT-rich DNA sequences (41), we next investigated the DNA binding characteristics of these compounds.…”
Section: Resultsmentioning
confidence: 99%
“…Even though the weakest DNA binder, pentamidine, showed the lowest LdTOPI inhibition capacity, there was no clear correlation established between DNA binding strength and LdTOPI inhibition within the test set, possibly due to the small number of compounds and a diversity of the core scaffold. However, at least, the mode of inhibition is thought to be mediated by binding to the substrate DNA based on data from previous crystallographic studies (28,29,41). In terms of potency, the effective concentrations of these compounds against LdTOP1 were relatively similar to or even higher than the EC 50 s of parasite inhibition.…”
Section: Resultsmentioning
confidence: 99%
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