The gallium(III)-salicylidene acylhydrazide complex shows synergistic anti-biofilm effect and inhibits toxin production by Pseudomonas aeruginosa.
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).
Department of Chemistry, Umeå University, 90187 Umeå, Sweden. Electronic address: olena.rzhepishevska@chem.umu.se.
Olena
O
Rzhepishevska
Department of Chemistry, Umeå University, 90187 Umeå, Sweden.
Shoghik
S
Hakobyan
Swedish Defense Research Institute (FOI), Cementvägen 20, 90182 Umeå, Sweden.
Barbro
B
Ekstrand-Hammarström
Swedish Defense Research Institute (FOI), Cementvägen 20, 90182 Umeå, Sweden.
Yvonne
Y
Nygren
Department of Chemistry, Umeå University, 90187 Umeå, Sweden.
Torbjörn
T
Karlsson
Swedish Defense Research Institute (FOI), Cementvägen 20, 90182 Umeå, Sweden.
Anders
A
Bucht
Department of Chemistry, Umeå University, 90187 Umeå, Sweden.
Mikael
M
Elofsson
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
D000081:Acetamides / Q000494:pharmacology*; D018441:Biofilms; D005708:Gallium / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology*; D006835:Hydrazones / Q000494:pharmacology*; D007956:Leukocidins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D009942:Organometallic Compounds / Q000494:pharmacology*; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D014774:Virulence / Q000187:drug effects; D037521:Virulence Factors / Q000096:biosynthesis
C000595546:2-oxo-2-(N-(2,4,6-trihydroxy-benzylidene)-hydrazino)-acetamide; D000081:Acetamides; D006834:Hydrazines; D006835:Hydrazones; D007956:Leukocidins; D009942:Organometallic Compounds; C510238:Pseudomonas aeruginosa Cytotoxins; D037521:Virulence Factors; D005708:Gallium
Bacteria; Biofilm; EXAFS; Gallium; Metal complex; Virulence