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Influence of Chelation Strength and Bacterial Uptake of Gallium Salicylidene Acylhydrazide on Biofilm Formation and Virulence by Pseudomonas aeruginosa
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
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2016 (Engelska)Ingår i: Journal of Inorganic Biochemistry, ISSN 0162-0134, E-ISSN 1873-3344, Vol. 160, s. 24-32Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Development of antibiotic resistance in bacteria causes major challenges for our society and has prompted a great need for new and alternative treatment methods for infection. One promising approach is to target bacterial virulence using for example salicylidene acylhydrazides (hydrazones). Hydrazones coordinate metal ions such as Fe(III) and Ga(III) through a five-membered and a six-membered chelation ring. One suggested mode of action is via restricting bacterial Fe uptake. Thus, it was hypothesized that the chelating strength of these substances could be used to predict their biological activity on bacterial cells. This was investigated by comparing Ga chelation strength of two hydrazone complexes, as well as bacterial Ga uptake, biofilm formation, and virulence in the form of production and secretion of a toxin (ExoS) by Pseudomonas aeruginosa. Equilibrium constants for deprotonation and Ga(III) binding of the hydrazone N′-(5-chloro-2-hydroxy-3-methylbenzylidene)-2,4-dihydroxybenzhydrazide (ME0329), with anti-virulence effect against P. aeruginosa, were determined and compared to bacterial siderophores and the previously described Ga(III) 2-oxo-2-[N-(2,4,6-trihydroxy-benzylidene)-hydrazino]-acetamide (Ga-ME0163) and Ga-citrate complexes. In comparison with these two complexes, it was shown that the uptake of Ga(III) was higher from the Ga-ME0329 complex. The results further show that the Ga-ME0329 complex reduced ExoS expression and secretion to a higher extent than Ga-citrate, Ga-ME0163 or the non-coordinated hydrazone. However, the effect against biofilm formation by P. aeruginosa, by the ME0329 complex, was similar to Ga-citrate and lower than what has been reported for Ga-ME0163.

Ort, förlag, år, upplaga, sidor
Elsevier, 2016. Vol. 160, s. 24-32
Nyckelord [en]
Gallium, Equilibrium constants, Virulence, Biofilm, Bacteria, UV–vis
Nationell ämneskategori
Kemi Biokemi och molekylärbiologi
Identifikatorer
URN: urn:nbn:se:umu:diva-107749DOI: 10.1016/j.jinorgbio.2016.04.010ISI: 000378965200003PubMedID: 27118030OAI: oai:DiVA.org:umu-107749DiVA, id: diva2:849356
Forskningsfinansiär
Vetenskapsrådet, 2011-3504Vetenskapsrådet, 2012-2976Tillgänglig från: 2015-08-28 Skapad: 2015-08-28 Senast uppdaterad: 2018-06-07Bibliografiskt granskad
Ingår i avhandling
1. Antivirulent and antibiofilm salicylidene acylhydrazide complexes in solution and at interfaces
Öppna denna publikation i ny flik eller fönster >>Antivirulent and antibiofilm salicylidene acylhydrazide complexes in solution and at interfaces
2015 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå University, 2015. s. 84
Nyckelord
Antivirulent, Antibiofilm, Hydrazones, Gallium, Pseudomonas aeruginosa, Type three secretion system, Equilibrium constant, Chemical equilibrium modelling, Spectrophotometric titration, UV-Vis
Nationell ämneskategori
Kemi
Identifikatorer
urn:nbn:se:umu:diva-107889 (URN)978-91-7601-307-6 (ISBN)
Disputation
2015-09-24, KB3B1 KBC, Umeå, 10:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2015-09-03 Skapad: 2015-08-28 Senast uppdaterad: 2018-06-07Bibliografiskt granskad

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Hakobyan, ShoghikRzhepishevska, OlenaBjörn, ErikBoily, Jean-FrançoisRamstedt, Madeleine

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