Research Article: Nutrient Limitation Governs Staphylococcus aureus Metabolism and Niche Adaptation in the Human Nose

Date Published: January 16, 2014

Publisher: Public Library of Science

Author(s): Bernhard Krismer, Manuel Liebeke, Daniela Janek, Mulugeta Nega, Maren Rautenberg, Gabriele Hornig, Clemens Unger, Christopher Weidenmaier, Michael Lalk, Andreas Peschel, Michael S. Gilmore.


Colonization of the human nose by Staphylococcus aureus in one-third of the population represents a major risk factor for invasive infections. The basis for adaptation of S. aureus to this specific habitat and reasons for the human predisposition to become colonized have remained largely unknown. Human nasal secretions were analyzed by metabolomics and found to contain potential nutrients in rather low amounts. No significant differences were found between S. aureus carriers and non-carriers, indicating that carriage is not associated with individual differences in nutrient supply. A synthetic nasal medium (SNM3) was composed based on the metabolomics data that permits consistent growth of S. aureus isolates. Key genes were expressed in SNM3 in a similar way as in the human nose, indicating that SNM3 represents a suitable surrogate environment for in vitro simulation studies. While the majority of S. aureus strains grew well in SNM3, most of the tested coagulase-negative staphylococci (CoNS) had major problems to multiply in SNM3 supporting the notion that CoNS are less well adapted to the nose and colonize preferentially the human skin. Global gene expression analysis revealed that, during growth in SNM3, S. aureus depends heavily on de novo synthesis of methionine. Accordingly, the methionine-biosynthesis enzyme cysteine-γ-synthase (MetI) was indispensable for growth in SNM3, and the MetI inhibitor DL-propargylglycine inhibited S. aureus growth in SNM3 but not in the presence of methionine. Of note, metI was strongly up-regulated by S. aureus in human noses, and metI mutants were strongly abrogated in their capacity to colonize the noses of cotton rats. These findings indicate that the methionine biosynthetic pathway may include promising antimicrobial targets that have previously remained unrecognized. Hence, exploring the environmental conditions facultative pathogens are exposed to during colonization can be useful for understanding niche adaptation and identifying targets for new antimicrobial strategies.

Partial Text

Staphylococcus aureus is a major cause of human invasive infections ranging from superficial skin and soft tissue infections to severe disseminated diseases such as sepsis and endocarditis [1]. S. aureus is also a human commensal and part of the microbiota in healthy individuals, which facilitates its access to sterile tissues via open wounds and catheter entry sites. S. aureus can be isolated from various human body surfaces such as the pharynx, axillae and perineum but its main ecological niche and reservoir is known for long to be the human nose [2]–[4]. In contrast, coagulase-negative staphylococci (CoNS), such as Staphylococcus epidermidis, have a much lower virulence potential and use different areas of the skin as their major habitats [5]. The basis of staphylococcal host and niche-specificity has remained unknown.

The metabolomics analysis of nasal secretions reveals that the human nose represents an environment with rather limited nutrient availability. The concentrations of glucose and amino acids are substantially lower in nasal secretions compared to human plasma of healthy individuals (glucose about 0.04–1 mM vs. 4–8 mM; amino acids about 0.65–2.2 mM vs. 2.6 to 4.3 mM, respectively) [38]. The sputum covering lung epithelia of cystic fibrosis (CF) patients, which are frequently infected by S. aureus[39], [40], contains similar concentrations of glucose and even higher concentrations of free amino acids than plasma (1.3 to 4.5 mM and 4.7 to 24.7 mM, respectively [41]. These differences in nutrient availability suggest that S. aureus requires different metabolic activities during colonization of the human nose or infection of sterile tissues. It is interesting to note that lactate, an abundant compound on skin with concentrations around 2.5 mM [42] and a product of S. aureus energy metabolism [43], was undetectable in nasal secretions. Accordingly, metabolites in the nasal habitat differ from those on skin, and S. aureus metabolism does not seem to affect much the nasal metabolome. Our data indicate that the concentration of many nutrients in nasal secretions varies between donors, but none of the differences could be associated with the S. aureus carrier status. Thus, factors other than nutrient supply, such as differences in epithelial immunity or ligands for S. aureus adhesins, may be responsible for the predisposition to the S. aureus carriage status.




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