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Antivirulent and antibiofilm salicylidene acylhydrazide complexes in solution and at interfaces
Umeå University, Faculty of Science and Technology, Department of Chemistry.
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.
Keyword [en]
Antivirulent, Antibiofilm, Hydrazones, Gallium, Pseudomonas aeruginosa, Type three secretion system, Equilibrium constant, Chemical equilibrium modelling, Spectrophotometric titration, UV-Vis
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:umu:diva-107889ISBN: 978-91-7601-307-6 (print)OAI: oai:DiVA.org:umu-107889DiVA: diva2:849571
Public defence
2015-09-24, KB3B1 KBC, Umeå, 10:00 (English)
Opponent
Supervisors
Available from: 2015-09-03 Created: 2015-08-28 Last updated: 2015-09-01Bibliographically approved
List of papers
1. The surface charge of anti-bacterial coatings alters motility and biofilm architecture
Open this publication in new window or tab >>The surface charge of anti-bacterial coatings alters motility and biofilm architecture
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2013 (English)In: Journal of Biomaterials Science. Polymer Edition, ISSN 0920-5063, E-ISSN 1568-5624, Vol. 1, no 6, 589-602 p.Article in journal (Refereed) Published
Abstract [en]

Bacterial biofilms affect many areas of human activity including food processing, transportation, public infrastructure, and most importantly healthcare. This study addresses the prevention of biofilms and shows that the surface charge of an abiotic substrate influences bacterial motility as well as the morphology and physiology of the biofilm. Grafting-from polymerisation was used to create polymer brush surfaces with different characteristics, and the development of Pseudomonas aeruginosa biofilms was followed using confocal microscopy. Interestingly, two types of biofilms developed on these surfaces: mushroom structures with high levels of cyclic diguanylate (c-di-GMP) were found on negatively charged poly (3-sulphopropylmethacrylate) (SPM) and zwitterionic poly (2-(methacryloyloxy)ethyl)dimethyl-3-sulphoproyl) ammonium hydroxide) (MEDSAH), while flat biofilms developed on glass, positively charged poly (2-(methacryloyloxy)-ethyl trimethyl ammonium chloride) (METAC), protein-repellent poly oligo(ethylene glycol methyl ether methacrylate) (POEGMA) and hydrophobic polymethylmethacrylate (PMMA). The results show that of all the surfaces studied, overall the negatively charged polymer brushes were most efficient in reducing bacterial adhesion and biofilm formation. However, the increased level of regulatory c-di-GMP in mushroom structures suggests that bacteria are capable of a quick physiological response when exposed to surfaces with varying physicochemical characteristics enabling some bacterial colonization also on negatively charged surfaces.

Place, publisher, year, edition, pages
RSC Publishing, 2013
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-70378 (URN)10.1039/c3bm00197k (DOI)000330134900004 ()
Funder
Carl Tryggers foundation Swedish Research Council
Available from: 2013-05-14 Created: 2013-05-14 Last updated: 2017-12-06Bibliographically approved
2. Proton and gallium(III) binding properties of a biologically active salicylidene acylhydrazide
Open this publication in new window or tab >>Proton and gallium(III) binding properties of a biologically active salicylidene acylhydrazide
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
Keyword
protonation, complex formation, gallium, pH titration, UV-VIS, equilibrium constants
National Category
Chemical Sciences Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-89585 (URN)10.1016/j.jinorgbio.2014.04.012 (DOI)000339303000002 ()24837332 (PubMedID)
Available from: 2014-06-04 Created: 2014-06-04 Last updated: 2017-12-05Bibliographically approved
3. The gallium(III)-salicylidene acylhydrazide complex shows synergistic anti-biofilm effect and inhibits toxin production by Pseudomonas aeruginosa
Open this publication in new window or tab >>The gallium(III)-salicylidene acylhydrazide complex shows synergistic anti-biofilm effect and inhibits toxin production by Pseudomonas aeruginosa
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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
Keyword
metal complex, gallium, virulence, biofilm, bacteria, EXAFS
National Category
Chemical Sciences Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-89584 (URN)10.1016/j.jinorgbio.2014.04.009 (DOI)000339303000001 ()24837331 (PubMedID)
Available from: 2014-06-04 Created: 2014-06-04 Last updated: 2017-12-05Bibliographically approved
4. Influence of Chelation Strength and Bacterial Uptake of Gallium Salicylidene Acylhydrazide on Biofilm Formation and Virulence by Pseudomonas aeruginosa
Open this publication in new window or tab >>Influence of Chelation Strength and Bacterial Uptake of Gallium Salicylidene Acylhydrazide on Biofilm Formation and Virulence by Pseudomonas aeruginosa
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2016 (English)In: Journal of Inorganic Biochemistry, ISSN 0162-0134, E-ISSN 1873-3344, Vol. 160, 24-32 p.Article in journal (Refereed) 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.

Place, publisher, year, edition, pages
Elsevier, 2016
Keyword
Gallium, Equilibrium constants, Virulence, Biofilm, Bacteria, UV–vis
National Category
Chemical Sciences Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-107749 (URN)10.1016/j.jinorgbio.2016.04.010 (DOI)000378965200003 ()27118030 (PubMedID)
Funder
Swedish Research Council, 2011-3504Swedish Research Council, 2012-2976
Available from: 2015-08-28 Created: 2015-08-28 Last updated: 2017-12-04Bibliographically approved
5. Preparation of Antifouling Polymer Brushes Functionalized with Gallium Salicylidene Acylhydrazide Complexes
Open this publication in new window or tab >>Preparation of Antifouling Polymer Brushes Functionalized with Gallium Salicylidene Acylhydrazide Complexes
(English)Manuscript (preprint) (Other academic)
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-107750 (URN)
Available from: 2015-08-28 Created: 2015-08-28 Last updated: 2015-09-01

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