There is an urgent requirement for the development of novel classes of antibacterial agents to combat the widespread phenomenon of antimicrobial resistance (AMR). In this setting, there is renewed interest in metal-based compounds as an alternative to conventional organic antibiotics.[1] A metal ion of our interest is Ga(III), which has a similar charge-to-size ratio and coordination preference to the biologically-essential Fe(III) ion. These properties allow Ga(III) to bind to biomolecules evolved to sequester and transport Fe(III) (e.g., bacterial siderophores, transferrin), which facilitates the uptake of Ga(III) into bacterial and mammalian cells. Unlike Fe(III) however, Ga(III) cannot undergo the cyclic redox activity akin to the Fe(III)/Fe(II) pair under physiological conditions, thus substitution of Ga(III) ions into Fe(III)-dependent metabolic pathways may result in inhibitory activities.[2] We are interested in the development of novel Ga(III) compounds as therapeutics to prevent and treat infections associated with multi-drug resistant bacteria.
Here, the synthesis and structure of novel gallium(III) compounds with composition [Ga(CH3)2(L)] and [Ga(L)3] (L = substituted flavonolate) are reported. The organogallium compounds exhibit inhibitory concentrations in the nanomolar range towards Klebsiella pneumoniae; a clinically-relevant, Gram-negative pathogen. The homoleptic [Ga(L)3] compounds exhibit 5-fold higher inhibitory concentrations towards Klebsiella pneumoniae; highlighting the requirement of the methyl ligands on the Ga(III) centre for enhanced antibacterial activity. The important influence of performing the assays in tissue culture medium, which better represents the mammalian host environment, on the in vitro antibacterial activity of the gallium-based compounds is discussed. These studies provide valuable insights into the structural requirements that will allow for the rational design and development of Ga(III) complexes with potent and selective antibacterial activities.