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Proton and gallium(III) binding properties of a biologically active salicylidene acylhydrazide
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
2014 (English)In: Journal of Inorganic Biochemistry, ISSN 0162-0134, E-ISSN 1873-3344, Vol. 138, 9-15 p.Article in journal (Refereed) Published
Abstract [en]

Bacterial biofilm formation causes a range of problems in our society, especially in health care. Salicylidene acylhydrazides (hydrazones) are promising antivirulence drugs targeting secretion systems used during bacterial infection of host cells. When mixed with the gallium ion they become especially potent as bacterial and biofilm growth-suppressing agents, although the mechanisms through which this occurs are not fully understood. At the base of this uncertainty lies the nature of hydrazone-metal interactions. This study addresses this issue by resolving the equilibrium speciation of hydrazone-gallium aqueous solutions. The protonation constants of the target 2-oxo-2-[N-(2,4,6-trihydroxy-benzylidene)-hydrazino]-acetamide (ME0163) hydrazone species and of its 2,4,6-trihydroxybenzaldehyde and oxamic acid hydrazide building blocks were determined by UV-visible spectrophotometry to achieve this goal. These studies show that the hydrazone is an excessively strong complexing agent for gallium and that its antivirulence properties are predominantly ascribed to monomeric 1:1Ga-ME0163 complexes of various Ga hydrolysis and ME0163 protonation states. The chelation of Ga(III) to the hydrazone also increased the stability of the compounds against acid-induced hydrolysis, making this group of compounds very interesting for biological applications where the Fe-antagonist action of both Ga(III) and the hydrazone can be combined for enhanced biological effect.

Place, publisher, year, edition, pages
Elsevier, 2014. Vol. 138, 9-15 p.
Keyword [en]
protonation, complex formation, gallium, pH titration, UV-VIS, equilibrium constants
National Category
Chemical Sciences Biochemistry and Molecular Biology
URN: urn:nbn:se:umu:diva-89585DOI: 10.1016/j.jinorgbio.2014.04.012ISI: 000339303000002PubMedID: 24837332OAI: diva2:721697
Available from: 2014-06-04 Created: 2014-06-04 Last updated: 2015-09-01Bibliographically approved
In thesis
1. Antivirulent and antibiofilm salicylidene acylhydrazide complexes in solution and at interfaces
Open this publication in new window or tab >>Antivirulent and antibiofilm salicylidene acylhydrazide complexes in solution and at interfaces
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The growing bacterial resistance against antibiotics creates a limitation for using traditional antibiotics and requests development of new approaches for treatment of bacterial infections. Among the bacterial infections that are most difficult to treat, biofilm-associated infections are one of the most hazardous. Consequently, the prevention of biofilm formation is a very important issue. One of the techniques that are widely investigated nowadays for this purpose is surface modification by polymer brushes that allows generating antifouling antibacterial surfaces. Previously, it was reported that salicylidene acylhydrazides (hydrazones) are good candidates as antivirulence drugs targeting the type three secretion system (T3SS). This secretion system is used by several Gramnegative pathogens, including Pseudomonas aeruginosa, to deliver toxins into a host cell. Furthermore, the chemical structure of these substances allows formation of complexes with metal ions, such as Fe3+ and Ga3+. The antibacterial activity of Ga3+ is well known and attributed to its similarity to the Fe3+ ion. It has also been shown that Ga3+ ions are able to suppress biofilm formation and growth in bacteria. In this thesis the chemistry of antibacterial and antivirulence Ga3+-Hydrazone complexes in solution was studied. First, to get insights in the solution chemistry, the protonation and the stability constants as well as the speciation of the Ga3+-Hydrazone complexes were determined. Additionally, a procedure for anchoring one of the hydrazone substances to antifouling polymer brushes was optimized, and the resulting surfaces were characterized. Results showed that the complexation with Ga3+ ions stabilizes the ligand and increases its solubility. Ga3+ ion binds to the hydrazone molecule forming a strong chelate that should be stable at physiological conditions. The different biological assays, such as Ga3+ uptake, antivirulence and antibiofilm effects, indicated very complex interaction of these complexes with the bacterial cell. Negatively charged and zwitterionic surfaces strongly reduced protein adsorption as well as biofilm formation. Therefore, the antifouling zwitterionic poly-[2-(methacryloyloxy)ethyl]dimethyl-3- sulfopropyl)-ammonium hydroxide (pMEDSAH) brushes were post-modified and successfully functionalized with bioactive substances via a block-copolymerization strategy. However, in order to maintain the availability of the bioactive substance after functionalization, the hydrophobic polyglycidylmethacrylate (pGMA) top block is probably better to functionalize with a lipophilic molecules to reduce diblock copolymer brush rearrangement.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2015. 84 p.
Antivirulent, Antibiofilm, Hydrazones, Gallium, Pseudomonas aeruginosa, Type three secretion system, Equilibrium constant, Chemical equilibrium modelling, Spectrophotometric titration, UV-Vis
National Category
Chemical Sciences
urn:nbn:se:umu:diva-107889 (URN)978-91-7601-307-6 (ISBN)
Public defence
2015-09-24, KB3B1 KBC, Umeå, 10:00 (English)
Available from: 2015-09-03 Created: 2015-08-28 Last updated: 2015-09-01Bibliographically approved

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