Influence of chelation strength and bacterial uptake of gallium salicylidene acylhydrazide on biofilm formation and virulence of Pseudomonas aeruginosa.
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.
Department of Chemistry, Umeå University, 90187 Umeå, Sweden.
Shoghik
S
Hakobyan
Department of Chemistry, Umeå University, 90187 Umeå, Sweden.
Olena
O
Rzhepishevska
Department of Chemistry, Umeå University, 90187 Umeå, Sweden.
Erik
E
Björn
Department of Chemistry, Umeå University, 90187 Umeå, Sweden.
Jean-François
JF
Boily
Department of Chemistry, Umeå University, 90187 Umeå, Sweden. Electronic address: madeleine.ramstedt@chem.umu.se.
Madeleine
M
Ramstedt
D036002:ADP Ribose Transferases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D018441:Biofilms / Q000187:drug effects / Q000254:growth & development; D001692:Biological Transport; D002614:Chelating Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000494:pharmacology*; D005708:Gallium / Q000737:chemistry*; D006835:Hydrazones / Q000138:chemical synthesis / Q000494:pharmacology*; D007700:Kinetics; D011522:Protons; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism / Q000472:pathogenicity; D014774:Virulence; D037521:Virulence Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis
D000900:Anti-Bacterial Agents; D001427:Bacterial Toxins; D002614:Chelating Agents; D056831:Coordination Complexes; D006835:Hydrazones; D011522:Protons; D037521:Virulence Factors; D005708:Gallium; D036002:ADP Ribose Transferases; C444820:exoenzyme S
Bacteria; Biofilm; Equilibrium constants; Gallium; UV–vis; Virulence