Enhanced antibacterial activity of dimethyl gallium quinolinolates toward drug-resistant Klebsiella pneumoniae in low iron environments

Abstract

A series of dimethylgallium quinolinolate [GaMe2L] (L = 5-chloroquinolinolate, 5, 7-dichloroquinolinolate, 5, 7-dibromoquinolinolate or 5, 7-doiodoquinolinolate) complexes, shown previously to be active toward the Leishmania parasite, have been studied for their antibacterial activity toward a reference and drug resistant strain of Klebsiella pneumoniae (KP). The assays were conducted in standard iron-rich LB media and in the iron depleted RPMI and RPMI-HS media to better understand the effect of Fe concentration on the activity of the Ga complexes. In LB broth the parent quinolinols and the gallium complexes were inactive up to the highest concentration tested, 100 μM. In the more physiologically relevant ‘iron-poor’ RPMI-HS media the quinolonols remained inactive, however, the gallium complexes showed exceptional activity in the range 48–195 nM. Only in RPMI without any added HS did both the quinolinols and the gallium complexes show good activity. The significant differences in activity across the various media types suggest that the unnaturally high iron content of conventional LB media may provide false negative results for potentially potent Ga therapeutics. A protein binding assay on the organometallic gallium complexes showed a much slower uptake of Ga by Fe-binding proteins than is typically observed for gallium salts. This indicates that their greater lipophilicity and greater hydrolytic stability could account for their increased biological activity in RPMI-HS media.