Resisting death by metal: metabolism and Cu/Zn homeostasis in bacteria

Abstract

Metal ions such as zinc and copper play important roles in host-microbe interactions and their availability can drastically affect the survival of pathogenic bacteria in a host niche. Mechanisms of metal homeostasis protect bacteria from starvation, or intoxication, defined as when metals are limiting, or in excess, respectively. In this mini-review, we summarise current knowledge on the mechanisms of resistance to metal stress in bacteria, focussing specifically on the homeostasis of cellular copper and zinc. This includes a summary of the factors that subvert metal stress in bacteria, which are independent of metal efflux systems, and commentary on the role of small molecules and metabolic systems as important mediators of metal resistance.

Keywords: copper; homeostasis; metabolism; metal; small molecules; zinc.

Figure 1.. Cu intoxication in bacteria and molecular rescue by small molecules.

(A) Cu intoxication causes a reduction (red arrows) in cellular glutathione, metal management [35] and reduction in viability at late stationary phase [38] in S. pyogenes. Cu-binding to histidine and cysteine residues in the catalytic site of GapA likely leads to a reduction in activity and subsequent flux through the fermentative pathway [35]. Growth inhibition in S. pyogenes undergoing Cu intoxication can be rescued by supplementation with the small molecules glutathione [35] or cysteine [38], likely due to chelation of excess Cu. (B) Cu binds to and destroys solvent-accessible Fe–S clusters in enzymes such as in IPMI and fumarase. This leads to growth inhibition of E. coli by a reduction in BCAA synthesis and reduced activity of multiple Fe–S enzymes [31,39], which can be partially restored by supplementing with BCAAs valine, leucine and isoleucine to bypass the BCAA synthesis block [39]. (C) Cu inactivates Fe–S cluster-containing GOGAT, impairing glutamate synthesis, which can be rescued by supplying exogenous glutamate or glutamine [31]. GAPDH/GapA, glyceraldehyde 3-phosphate dehydrogenase; G3P, glyceraldehyde-3-phosphate; Pi, inorganic phosphate; 1,3-BP, 1,3-bisphospho-d-glycerate; NAD⁺/NADH/NADP⁺/NADPH, nicotinamide adenine dinucleotide cofactors; SH, thiol group; 2-IPM, 2-isopropylmalate; 3-IPM, 3-isopropylmalate; IPMI, isopropylmalate isomerase; BCAA, branched-chain amino acid; GOGAT, glutamine oxoglutarate aminotransferase; 2-OG, 2-oxoglutarate; Cys, cysteine; Gly, glycine; Val, valine; Ile, isoleucine; Leu, leucine; Glu, glutamate; Gln, glutamine.

Figure 2.. Chemical structures of small molecules that influence metal homeostasis.

Certain molecules including glutathione, cysteine, histidine and ornithine can act to rescue bacteria from metal toxicity, whereas others can enhance metal toxicity, including disulfiram, N,N-dimethyldithiocarbamate (DMDC), PBT2 and staphylopine. ChEBI [99] structures: glutathione 16 856; cysteine 17 561; histidine 15 971; ornithine 15 729; disulfiram 4659; N′N′-dimethyldithiocarbamate 84 293; staphylopine 141 669.