Influence of chelation strength and bacterial uptake of gallium salicylidene acylhydrazide on biofilm formation and virulence of Pseudomonas aeruginosa

Abstract

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.

Synthesis, Structural Characterization and Antimicrobial Evaluation of Ruthenium Complexes with Heteroaromatic Carboxylic Acids

“…Biologically active metal complexes have gained special significance due to the need for the prevention of resistance of bacterial strains. Recently, several Cu(II), Ga(III), Zn(II), Mn(II), Ag(I), Au(III) and Ru(II) complexes with bioactive ligands have been tested as potential antibiofilm and antimicrobial agents . Among above mentioned metal complexes, ruthenium compounds are promising for medicinal and biotechnological applications as they present unique properties: (i) multiple oxidation states (II, III and IV), which are accessible in physiological conditions; (ii) favorable ligand‐exchange kinetics; (iii) multiple cytotoxic routes involving the competing processes of extracellular protein binding (active transport), due to the ability to mimic iron and cellular uptake (passive diffusion); (iv) different molecular pathways involving the concurrent intercalation and covalent binding with DNA and binding to extracellular sites inducing conformational modifications; (v) numerous synthetic opportunities for modifying the biological activity which depends on both the oxidation state of the metal center and the associated ligands surrounding it.…”

New alternative therapeutic strategies against Pseudomonas aeruginosa, an opportunistic multi-resistant pathogen with a myriad of virulence factors

“…Several studies focus on the development of novel formulations to deliver gallium, including polymeric or solid materials that offer a slow release of gallium [75]; co-encapsulated to deliver gallium along with a conventional antibiotic; as well as gallium complexed with biological and synthetic chelating agents [74,76,77]. Banin et al (2008) combines a strong siderophore, desferrioxamine (DFO), with gallium (DFO-Ga) as a Trojan horse delivery system.…”

Chelation in Antibacterial Drugs: From Nitroxoline to Cefiderocol and Beyond

“…The chelating strength of the substances is being used to predict their biological activity on bacterial cells [ 136 , 137 ]. The search for alternative substances to small molecule antimicrobials has identified chelation therapy as one of the main approaches, with the potential for the treatment and prevention of antibiotic-resistant infections [ 138 ] and for the design of advanced antimicrobial approaches [ 139 ].…”