Inter- and Intraspecies Metabolite Exchange Promotes Virulence of Antibiotic-Resistant Staphylococcus aureus

Neal D. Hammer, James E. Cassat, Michael J. Noto, Lisa J. Lojek, Ashley D. Chadha,

Jonathan E. Schmitz, C. Buddy Creech, and Eric P. Skaar,

Cell Host & Microbe October, 2014; 16: 531–537.

Speaker: Yi-Wen Liu (劉怡彣)                             Time: 14:10~15:00, Mar. 11, 2015

Commentator: Dr. Lien-I Hor (何漣漪 老師)     Place: Room 601

Abstract

Small colony variants (SCVs) of Staphylococcus aureus have been implicated in chronic recurrent infections such as osteomyelitis and cystic fibrosis (CF).  SCVs are characterized by impaired growth and limited virulence. Furthermore, SCVs are frequently resistant to various antibiotics. The most well studied mechanisms leading to the SCV phenotype so far are the hemin- andmenadione-dependent SCVs, which are resistant to aminoglycosides. In this study, the authors found that coculture of two aminoglycoside-resistant S. aureus SCVs which were deficient in the biosynthetic pathways for heme (ΔhemB) or menaquinone (ΔmenE) can enhance growth, virulence factor production, cytotoxicity, but failed to completely restore antibiotic susceptibility to wild-type levels. These results indicate that distinct SCVs can complement each other to enhance growth through metabolite exchange. Additionally, increased bacterial density in ΔhemB-ΔmenEcocultures was accompanied by enhanced activation of quorum sensing mediated by the accessory gene regulator (agr) system which controls the virulence factor production. As compared to supernatants from wild-type, ΔhemB, and ΔmenE, supernatants obtained from ΔhemB-ΔmenE coculture incite significantly more osteoblast cell death. Moreover, coinfection with ΔhemB-ΔmenEresults in increased intraosseous bacterial burdens and bone destruction in a murine osteomyelitis model. S. aureus SCVs can also be generated by exposure to either gentamicin (SCV^gent) orpyocyanin (SCV^pyo). Pyocyanin is an exotoxin secreted from P. aeruginosa, which hinders S. aureus respiration. Coculture of SCV^gent with SCV^pyo increases growth over each single SCV even in the presence of gentamicin. Finally, the authors isolated bacteria from the respiratory tract. The human upper respiratory microbiota is capable of enhancing the growth of S. aureus ΔhemB, ΔmenEor both, suggesting that metabolite exchange may also occur within human microbial communities. In conclusion, inter- and intraspecies community interactions offset fitness costs and enable S. aureus to develop antibiotic resistance without loss of virulence.

References

1.     Kahl BC. 2013. Small colony variants (SCVs) of Staphylococcus aureus - a bacterial survival strategy. Infect Genet Evol. 21:515-22.