Ubiquitous selection for mecA in community-associated MRSA across diverse chemical environments

Olga Snitser,Laura K Stone,Roy Kishony,Haleli Sharir,Kathy K Wang,Dor Russ,Haim M Barr,Noga Kozer,Galit Cohen

doi:10.1038/s41467-020-19825-3

Abstract

Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is threatening public health as it spreads worldwide across diverse environments. Its genetic hallmark, the mecA gene, confers resistance to many β-lactam antibiotics. Here, we show that, in addition, mecA provides a broad selective advantage across diverse chemical environments. Competing fluorescently labelled wild-type and mecA-deleted CA-MRSA USA400 strains across ~57,000 compounds supplemented with subinhibitory levels of the β-lactam drug cefoxitin, we find that mecA provides a widespread advantage across β-lactam and non β-lactam antibiotics, non-antibiotic drugs and even diverse natural and synthetic compounds. This advantage depends on the presence of cefoxitin and is strongly associated with the compounds’ physicochemical properties, suggesting that it may be mediated by differential compounds permeability into the cell. Indeed, mecA protects the bacteria against increased cell-envelope permeability under subinhibitory cefoxitin treatment. Our findings suggest that CA-MRSA success might be driven by a cell-envelope mediated selective advantage across diverse chemical compounds.

Highlights

Community-associated methicillin-resistant Staphylococcus aureus (CA-Methicillin-resistant Staphylococcus aureus (MRSA)) is threatening public health as it spreads worldwide across diverse environments
It is generally acknowledged that these specific factors are not sufficient to understand the widespread success of Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA), suggesting that there might be additional and more general mechanisms that confer a selective advantage across diverse environments
The assay is based on a direct competition between two strains: a wild-type community-associated methicillin-resistant S. aureus (MW2, a CAMRSA strain carrying Staphylococcal Cassette Chromosome mec (SCCmec) type IV, “mecA+”) and the same strain with the mecA gene deleted (MW2 ΔmecA, “mecA−”)

Summary

Introduction

Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is threatening public health as it spreads worldwide across diverse environments. Competing fluorescently labelled wild-type and mecA-deleted CA-MRSA USA400 strains across ~57,000 compounds supplemented with subinhibitory levels of the β-lactam drug cefoxitin, we find that mecA provides a widespread advantage across β-lactam and non β-lactam antibiotics, non-antibiotic drugs and even diverse natural and synthetic compounds. This advantage depends on the presence of cefoxitin and is strongly associated with the compounds’ physicochemical properties, suggesting that it may be mediated by differential compounds permeability into the cell. Unlike HAMRSA, strains of CA-MRSA are typically susceptible to non-βlactam antibiotics[2] They have rapidly spread worldwide, indicating a strong selective advantage across diverse environments. It is unknown whether these previously observed patterns of balanced selection, both for and against a resistant gene[21], apply for mecA

Methods

Results

Conclusion