The Staphylococcus aureus Cystine Transporters TcyABC and TcyP Facilitate Nutrient Sulfur Acquisition during Infection

Abstract

Staphylococcus aureus is a significant human pathogen due to its capacity to cause a multitude of diseases. As such, S. aureus efficiently pillages vital nutrients from the host; however, the molecular mechanisms that support sulfur acquisition during infection have not been established. One of the most abundant extracellular sulfur-containing metabolites within the host is cysteine, which acts as the major redox buffer in the blood by transitioning between reduced and oxidized (cystine) forms. We therefore hypothesized that S. aureus acquires host-derived cysteine and cystine as sources of nutrient sulfur during systemic infection. To test this hypothesis, we used the toxic cystine analogue selenocystine to initially characterize S. aureus homologues of the Bacillus subtilis cystine transporters TcyABC and TcyP. We found that genetic inactivation of both TcyA and TcyP induced selenocystine resistance. The double mutant also failed to proliferate in medium supplemented with cystine, cysteine, or N-acetyl cysteine as the sole sulfur source. However, only TcyABC was necessary for proliferation in defined medium containing homocystine as the sulfur source. Using a murine model of systemic infection, we observed tcyP-dependent competitive defects in the liver and heart, indicating that this sulfur acquisition strategy supports proliferation of S. aureus in these organs. Phylogenetic analyses identified TcyP homologues in many pathogenic species, implying that this sulfur procurement strategy is conserved. In total, this study is the first to experimentally validate sulfur acquisition systems in S. aureus and establish their importance during pathogenesis.

Proteomics of Campylobacter jejuni Growth in Deoxycholate Reveals Cj0025c as a Cystine Transport Protein Required for Wild-type Human Infection Phenotypes

“…Specific transporters for most Cys-dipeptides have not been identified. In DOC, we observed elevated abundance of a putative sodium:dicarboxylate symporter, Cj0025c, which shares significant sequence similarity to the TcyP family of bacterial Cys-Cys transporters ( 44 , 51 ). Deletion of cj0025c attenuated Cys-Cys uptake.…”

“…S6 ). TcyP is a Cys-Cys transporter required for sulfur uptake ( 44 , 51 ). qPCR confirmed that the increased abundance of Cj0025c was consistent with transcription of cj0025c during DOC growth (10.63-fold increased cj0025c expression; Fig.…”

Rapid and strain-specific resistance evolution ofStaphylococcus aureusagainst inhibitory molecules secreted byPseudomonas aeruginosa

“…While mutations in this gene were unique to JE2, they surfaced in seven clones in four out of the five JE2 populations. Deletion of tcyA leads to resistance against the toxic cystine analogue selenocystine in SA (Lensmire et al 2020). While PA strain PAO1 indeed contains the selenocysteine synthesis cluster, it is currently not known how its expression is controlled and whether selenocystine is deployed against competitors.…”

Vibrio fischeri imports and assimilates sulfate during symbiosis with Euprymna scolopes

“…Our report represents part of an expanding body of literature that highlights the importance of sulfur acquisition and its regulation for bacterial growth within a host. For example, the human pathogen Staphylococcus aureus scavenges cystine within heart and liver infections (Lensmire et al., 2020). To import cystine, S. aureus expresses TcyP symporter and TcyABC, with either necessary for normal fitness during heart infections but only TcyP contributing to fitness within liver infections.…”