Change search
ReferencesLink to record
Permanent link

Direct link
The gallium(III)-salicylidene acylhydrazide complex shows synergistic anti-biofilm effect and inhibits toxin production by Pseudomonas aeruginosa
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Swedish Defense Research Institute (FOI), Umeå, Sweden.
Swedish Defense Research Institute (FOI), Umeå, Sweden.
Show others and affiliations
2014 (English)In: Journal of Inorganic Biochemistry, ISSN 0162-0134, E-ISSN 1873-3344, Vol. 138, 1-8 p.Article in journal (Refereed) Published
Abstract [en]

Bacterial biofilms cause a range of problems in many areas and especially in health care. Biofilms are difficult to eradicate with traditional antibiotics and consequently there is a need for alternative ways to prevent and/or remove bacterial biofilms. Furthermore, the emergence of antibiotic resistance in bacteria creates a challenge to find new types of antibiotics with a lower evolutionary pressure for resistance development. One route to develop such drugs is to target the so called virulence factors, i.e. bacterial systems used when bacteria infect a host cell. This study investigates synergy effects between Ga(III) ions, previously reported to suppress biofilm formation and growth in bacteria, and salicylidene acylhydrazides (hydrazones) that have been proposed as antivirulence drugs targeting the type three secretion system used by several Gram-negative pathogens, including Pseudomonas aerugionosa, during bacterial infection of host cells. A library of hydrazones was screened for: Fe(III) binding, enhanced anti-biofilm effect with Ga(III) on P. aeruginosa, and low cytotoxicity to mammalian cells. The metal coordination for the most promising ligand, 2-Oxo-2-[N-(2,4,6-trihydroxy-benzylidene)-hydrazino]-acetamide (ME0163) with Ga(III) was investigated using extended X-ray absorption fine structure spectroscopy as well as density functional theory. The results showed that Ga(III) chelates the hydrazone with 5- and 6-membered chelating rings, and that the Ga(III)-ME0163 complex enhanced the antibiofilm effect of Ga(III) while suppressing the type three secretion system in P. aeruginosa. The latter effect was not observed for the hydrazone alone and was similar for Ga(III)-citrate and Ga(III)-ME0163 complexes, indicating that the inhibition of virulence was caused by Ga(III).

Place, publisher, year, edition, pages
Elsevier, 2014. Vol. 138, 1-8 p.
Keyword [en]
metal complex, gallium, virulence, biofilm, bacteria, EXAFS
National Category
Chemical Sciences Biochemistry and Molecular Biology
URN: urn:nbn:se:umu:diva-89584DOI: 10.1016/j.jinorgbio.2014.04.009ISI: 000339303000001PubMedID: 24837331OAI: diva2:721696
Available from: 2014-06-04 Created: 2014-06-04 Last updated: 2016-05-23Bibliographically 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

Open Access in DiVA

fulltext(2630 kB)203 downloads
File information
File name FULLTEXT01.pdfFile size 2630 kBChecksum SHA-512
Type fulltextMimetype application/pdf

Other links

Publisher's full textPubMed

Search in DiVA

By author/editor
Rzhepishevska, OlenaHakobyan, ShoghikKarlsson, TorbjörnBucht, AndersElofsson, MikaelBoily, Jean-FrançoisRamstedt, Madeleine
By organisation
Department of ChemistryPulmonary Medicine
In the same journal
Journal of Inorganic Biochemistry
Chemical SciencesBiochemistry and Molecular Biology

Search outside of DiVA

GoogleGoogle Scholar
Total: 203 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 220 hits
ReferencesLink to record
Permanent link

Direct link