Microaerobic conditions and the complex regulation of natural competence in Staphylococcus aureus
Authors: Feng Shi Yuan , Hauck Yolande , Morgene Fedy , Mohammedi Roza , Mirouze Nicolas 
Published: April 2022

SummaryTo perform genetic transformation, one of the three main Horizontal Gene Transfer mechanisms leading to virulence and antibiotic resistance genes acquisition, bacteria need to enter a physiological differentiated state called natural competence. Diverse environmental and cellular cues have been shown to trigger complex regulatory pathways ultimately activating central competence regulators controlling the expression of the genetic transformation genes. Interestingly, new bacteria displaying such aptitude are often discovered, and one of the latest is the human pathogen Staphylococcus aureus. However, a clear understanding of the environmental signals, regulatory pathways and central regulators involved in the development of competence in S. aureus is not yet available.Here, using an original optimized protocol to naturally induce competence in planktonic cells, leading to improved transformation efficiencies (up to 5.10−6), we showed that the three putative central competence regulators identified in S. aureus are all essential for a complete development of competence. We also found that genes involved in genetic transformation can be divided in several classes depending on the regulators controlling their expression. In addition, we showed that oxygen availability is an important signal leading to competence development through the induction of one of the three central regulators. Our results demonstrate the complexity of competence development in S. aureus, in comparison to other historical model organisms. We anticipate our findings to be a starting point for proving the importance of natural competence and genetic transformation for S. aureus genomic plasticity. Furthermore, we also believe that our data will allow us to elucidate the environmental conditions leading to antibiotic resistance acquisitions in vivo, in this important human pathogen.Introductory paragraphStaphylococcus aureus has become over the years an important public health concern, due to a large range of infections and the emergence of outbreaks associated to antibiotic multi-resistant strains. S. aureus remarkable adaptive powers have been acquired through the acquisition of new genetic sequences, thanks to Horizontal Gene Transfer (HGT). The recent demonstration of the capacity of S. aureus to induce natural competence for genetic transformation prompted scientists to investigate this important mode of HGT in this new model organism in the field. Few key reports have already established that the development of competence in S. aureus might be complex, involving several potential master regulators, activated in response to multiple environmental signals and regulatory pathways.In this study, we deciphered, thanks to the design of an optimized protocol, the complexity of the regulatory pathways leading to the development of competence as well as its true potential for S. aureus’s genomic plasticity in vivo. In addition, we clearly demonstrated that natural competence develops in response to oxygen limitation, a key environmental signal for a facultative anaerobe organism such as S. aureus.