Highly selective organo-gallium hydroxamate mediated inhibition of antibiotic resistant Klebsiella pneumoniae

Abstract

Five complexes of gallium derived from hydroxamic acids have been synthesised, characterised, and their anti-bacterial activity and mammalian cell toxicity established. These are three metal-organic complexes; [Ga(BPHA]₃ 1, [Ga(BHA-H]₃ 2, [Ga(SHA-H₂)(SHA-H)]₃ 3, and two heteroleptic organometallic complexes [GaMe₂(BPHA)] 4, and [GaMe(BHA-H)₂] 5, along with the iron complex [Fe(BPHA)₃] 6 (BPHA-H = N-benzoyl-N-phenylhydroxamic acid, BHA-H2 = phenylhydroxamic acid, and SHA-H3 = salicylhydroxamic acid). Solid-state structures of 1, 4 – 6 were identified by single-crystal X-ray crystallography. Complexes 1 and 6 adopt an octahedral geometry at the metal centre, while the organometallic complexes 4 and 5 adopt, respectively, tetrahedral and trigonal bipyramidal geometry. The solution and solid-state chemistry of complex 3 was found to differ: the solution state is composed of an equilibrium mixture of the bis-complexed hydroximate-hydroxamate species and the homoleptic tris-hydroxamate species, with the solid state preferring the bis-complexed hydroximate-hydroxamate composition. The methyl gallium complexes 4 and 5 differed in their preferred composition with 4 forming the expected dimethyl hydroxamate complex while 5 stabilises as the methyl bis-hydroxamate complex. Complexes were tested for the anti-microbial activity against a series of Gram-positive and Gram-negative bacteria, with an emphasis on the Gram-negative Klebsiella pneumoniae. While the metal-organic complexes 1, 2, 3 and 6 showed little to no activity towards either the bacteria or mammalian cells, the alkyl gallium complexes 4 and 5 were found to have exceptional activity toward K. pneumoniae in RPMI-HS media with MIC values of 78 nM. Interestingly, [GaMe₂(OH)] also showed significant activity with an MIC of 156 nM.