Abstract

Faster growing and more virulent strains of methicillin resistant Staphylococcus aureus (MRSA) are increasingly displacing highly resistant MRSA. Elevated fitness in these MRSA is often accompanied by decreased and heterogeneous levels of methicillin resistance; however, the mechanisms for this phenomenon are not yet fully understood. Whole genome sequencing was used to investigate the genetic basis of this apparent correlation, in an isogenic MRSA strain pair that differed in methicillin resistance levels and fitness, with respect to growth rate. Sequencing revealed only one single nucleotide polymorphism (SNP) in the diadenylate cyclase gene dacA in the faster growing but less resistant strain. Diadenylate cyclases were recently discovered to synthesize the new second messenger cyclic diadenosine monophosphate (c-di-AMP). Introduction of this mutation into the highly resistant but slower growing strain reduced resistance and increased its growth rate, suggesting a direct connection between the dacA mutation and the phenotypic differences of these strains. Quantification of cellular c-di-AMP revealed that the dacA mutation decreased c-di-AMP levels resulting in reduced autolysis, increased salt tolerance and a reduction in the basal expression of the cell wall stress stimulon. These results indicate that c-di-AMP affects cell envelope-related signalling in S. aureus. The influence of c-di-AMP on growth rate and methicillin resistance in MRSA indicate that altering c-di-AMP levels could be a mechanism by which MRSA strains can increase their fitness levels by reducing their methicillin resistance levels.

Highlights

  • Infections with methicillin resistant Staphylococcus aureus (MRSA) have severely impaired treatment outcomes and are cost intensive for the healthcare system

  • In previous studies a highly and homogeneously resistant MRSA was constructed by introducing the staphylococcal cassette chromosome mec (SCCmec) element from strain COL into the methicillin sensitive S. aureus (MSSA) strain BB255 [53,54]

  • Rescue from the fitness burden was accompanied by reduced, heterogeneous resistance to oxacillin [54]; a phenotype observed in CA-MRSA strains [4]

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Summary

Introduction

Infections with methicillin resistant Staphylococcus aureus (MRSA) have severely impaired treatment outcomes and are cost intensive for the healthcare system. MRSA were restricted to healthcare settings with high antibiotic pressure. These healthcareassociated (HA)-MRSA strains generally displayed low heterogeneous resistance profiles, whereby only small subpopulations could survive at high beta-lactam concentrations. HA-MRSA strains possessing very high beta-lactam minimum inhibitory concentrations (MICs) emerged, such as E-MRSA 16 (ST32MRSA-II) or the Iberian clone (ST247-MRSA-I), which successfully spread in hospitals all over the world (for reviews see [1,2]). CA-MRSA typically have relatively low oxacillin MICs, but their heterogeneous resistance profiles include higherresistant subpopulations of bacteria that can cause treatment failure. CA-MRSA-like clones are increasingly displacing conventional, previously successful, HA-MRSA clones in hospitals [6]

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