Old dogs, new tricks: New insights into the iron/manganese superoxide dismutase family.

Superoxide dismutases (SODs) are ancient enzymes of widespread importance present in all domains of life. Many insights have been gained into these important enzymes over the 50 years since their initial description, but recent studies in the context of microbial pathogenesis have resulted in findings that challenge long established dogmas. The repertoire of SODs that bacterial pathogens encode is diverse both in number and in metal dependencies, including copper, copper and zinc, manganese, iron, and cambialistic enzymes. Other bacteria also possess nickel dependent SODs. Compartmentalization of SODs only partially explains their diversity. The need for pathogens to maintain SOD activity across distinct hostile environments encountered during infection, including those limited for essential metals, is also a driver of repertoire diversity. SOD research using pathogenic microbes has also revealed the apparent biochemical ease with which metal specificity can change within the most common family of SODs. Collectively, these studies are revealing the dynamic nature of SOD evolution, both that of individual SOD enzymes that can change their metal specificity to adapt to fluctuating cellular metal availability, and of a cell's repertoire of SOD isozymes that can be differentially expressed to adapt to fluctuating environmental metal availability in a niche.

Mobilization of vitamin B12 transporters alters competitive dynamics in a human gut microbe.

The functional and genomic diversity of the human gut microbiome is shaped by horizontal transfer of mobile genetic elements (MGEs). Characterized MGEs can encode genes beneficial for their host's self-defense (e.g., antibiotic resistance) or ability to compete for essential or limited resources (e.g., vitamins). Vitamin B12 and related compounds (corrinoids) are critical nutrients that enable colonization by members of the common gut microbe phylum, the Bacteroidetes. Herein, we identify a distinct class of MGEs in the Bacteroidetes responsible for the mobilization and exchange of the genes required for transport of corrinoids, a group of cyclic tetrapyrrole cofactors including vitamin B12 (btuGBFCD). This class includes two distinct groups of conjugative transposons (CTns) and one group of phage. Conjugative transfer and vitamin B12 transport activity of two of the CTns were confirmed in vitro and in vivo, demonstrating the important role MGEs play in distribution of corrinoid transporters in the Bacteroidetes.

Intracellular Accumulation of Staphylopine Can Sensitize Staphylococcus aureus to Host-Imposed Zinc Starvation by Chelation-Independent Toxicity.

The host restricts the availability of zinc to prevent infection. To overcome this defense, Staphylococcus aureus and Pseudomonas aeruginosa rely on zincophore-dependent zinc importers. Synthesis of the zincophore staphylopine by S. aureus and its import are both necessary for the bacterium to cause infection. In this study, we sought to elucidate how loss of zincophore efflux impacts bacterial resistance to host-imposed zinc starvation. In culture and during infection, mutants lacking CntE, the staphylopine efflux pump, were more sensitive to zinc starvation imposed by the metal-binding immune effector calprotectin than those lacking the ability to import staphylopine. However, disruption of staphylopine synthesis reversed the enhanced sensitivity phenotype of the ΔcntE mutant to calprotectin, indicating that intracellular toxicity of staphylopine is more detrimental than the impaired ability to acquire zinc. Unexpectedly, intracellular accumulation of staphylopine does not increase the expression of metal importers or alter cellular metal concentrations, suggesting that, contrary to prevailing models, the toxicity associated with staphylopine is not strictly due to intracellular chelation of metals. As P. aeruginosa and other pathogens produce zincophores with similar chemistry, our observations on the crucial importance of zincophore efflux are likely to be broadly relevant.IMPORTANCEStaphylococcus aureus and many other bacterial pathogens rely on metal-binding small molecules to obtain the essential metal zinc during infection. In this study, we reveal that export of these small molecules is critical for overcoming host-imposed metal starvation during infection and prevents toxicity due to accumulation of the metal-binding molecule within the cell. Surprisingly, we found that intracellular toxicity of the molecule is not due to chelation of cellular metals.