A widespread SCCmec-located gene cluster protects MRSA against toxic polysulfide

Colonization of the human body presents challenges for opportunistic pathogens, which must overcome host defense mechanisms, antimicrobial compounds, and competition with the commensal microbiota. One of these opportunistic pathogens is Staphylococcus aureus (S. aureus), with methicillin-resistant S. aureus (MRSA) strains being one of the most common antibiotic-resistant nosocomial pathogens, responsible for millions of life-threatening infections worldwide8. S. aureus often colonizes mucosal surfaces of the human body and is therefore exposed to environmental stress factors, including hydrogen sulfide (H2S). H2S is ubiquitous in the human body, and while low concentrations act as a signaling molecule, high concentrations are toxic. The elevated H2S levels are primarily a consequence of bacterial sulfur compound metabolism. On mucosal surfaces, such as the nose and gut, H₂S concentrations can reach up to 0.4 mM9 and between 0.3–3.4 mM10,11, respectively, due to the degradation of sulfated sugar residues and l-cysteine from mucin12. Under oxic conditions, which prevail on mucosal surfaces13, H₂S oxidizes into highly reactive polysulfides, creating another toxic stressor for the bacteria. While it is known that S. aureus protects itself from H₂S via its cst gene cluster (tauE, cstR, cstA, cstB, sqr)14, the detoxification of polysulfides is virtually unknown. We showed that S. aureus uses an SQR-independent variant of the cst pathway to detoxify polysulfides. Furthermore, our research revealed that the cst gene cluster is heterogeneously distributed in staphylococcal genomes, with multiple clinically relevant SCCmec types introducing an additional cst (cst2, without sqr) into the genomes of MRSA strains. Phenotypic analyses of a wide range of clinical and laboratory-derived strains demonstrated that the additional cst2 confers high polysulfide tolerance to MRSA, providing a significant fitness advantage in polysulfide-rich environments that results in the displacement of MSSA strains in direct intraspecies competition.

8 Murray et al. (2022): in: The Lancet 399, 629–655

9 Ikeda et al. (2019): in: Molecules (Basel, Switzerland) 24

10 Braccia et al. (2021): in: Frontiers in microbiology 12: 705583

11 Dordević et al. (2021): in: Journal of advanced research 27: 55–69

12 Stümmer et al. (2023): in: Antioxidants (Basel, Switzerland) 12

13 Espey (2013): in: Free radical biology & medicine 55: 130–140

14 Shen, et al. (2015): in: Biochemistry 54 29, 4542–4554