Abstract
ABSTRACTStaphylococcus aureus is the leading cause of skin and soft tissue infections, bacteremia, osteomyelitis, and endocarditis in the developed world. The ability of S. aureus to cause substantial disease in distinct host environments is supported by a flexible metabolism that allows this pathogen to overcome challenges unique to each host organ. One feature of staphylococcal metabolic flexibility is a branched aerobic respiratory chain composed of multiple terminal oxidases. Whereas previous biochemical and spectroscopic studies reported the presence of three different respiratory oxygen reductases (o type, bd type, and aa3 type), the genome contains genes encoding only two respiratory oxygen reductases, cydAB and qoxABCD. Previous investigation showed that cydAB and qoxABCD are required to colonize specific host organs, the murine heart and liver, respectively. This work seeks to clarify the relationship between the genetic studies showing the unique roles of the cydAB and qoxABCD in virulence and the respiratory reductases reported in the literature. We establish that QoxABCD is an aa3-type menaquinol oxidase but that this enzyme is promiscuous in that it can assemble as a bo3-type menaquinol oxidase. However, the bo3 form of QoxABCD restricts the carbon sources that can support the growth of S. aureus. In addition, QoxABCD function is supported by a previously uncharacterized protein, which we have named CtaM, that is conserved in aerobically respiring Firmicutes. In total, these studies establish the heme A biosynthesis pathway in S. aureus, determine that QoxABCD is a type aa3 menaquinol oxidase, and reveal CtaM as a new protein required for type aa3 menaquinol oxidase function in multiple bacterial genera.
Highlights
Staphylococcus aureus is the leading cause of skin and soft tissue infections, bacteremia, osteomyelitis, and endocarditis in the developed world
It is shown that the S. aureus cytochrome bd is resistant to cyanide below 1 mM and that the QoxABCD enzyme exists in two forms
This gene, which we name ctaM, is adjacent to the gene encoding the heme O synthase, ctaB. These results define the molecular requirements for terminal oxidase function in S. aureus, provide an explanation for the previous observations describing the presence of an o-type reductase in the staphylococcal respiratory chain, and establish a conserved protein involved in terminal oxidase assembly
Summary
Staphylococcus aureus is the leading cause of skin and soft tissue infections, bacteremia, osteomyelitis, and endocarditis in the developed world. We identify a new gene in the S. aureus genome that is conserved in many Firmicutes and is required for the assembly of functional QoxABCD in any form This gene (locus NWMN_0982), which we name ctaM, is adjacent to the gene encoding the heme O synthase, ctaB. These results define the molecular requirements for terminal oxidase function in S. aureus, provide an explanation for the previous observations describing the presence of an o-type reductase in the staphylococcal respiratory chain, and establish a conserved protein involved in terminal oxidase assembly. These results establish that qoxABCD encodes a cyanide-sensitive, a-type reductase
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