The Role of ArlRS and VraSR in Regulating Ceftaroline Hypersusceptibility in Methicillin-Resistant Staphylococcus aureus

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The Role of ArlRS and VraSR in Regulating Ceftaroline Hypersusceptibility in Methicillin-Resistant Staphylococcus aureus

VILLANUEVA SAN MARTIN, Maite, et al.

Abstract

Methicillin-resistant Staphylococcus aureus infections are a global health problem. New control strategies, including fifth-generation cephalosporins such as ceftaroline, have been developed, however rare sporadic resistance has been reported. Our study aimed to determine whether disruption of two-component environmental signal systems detectably led to enhanced suscepti-bility to ceftaroline in S. aureus CA-MRSA strain MW2 at sub-MIC concentrations where cells normally continue to grow. A collection of sequential mutants in all fifteen S. aureus non-essential two-component systems (TCS) was first screened for ceftaroline sub-MIC susceptibility, using the spot population analysis profile method. We discovered a role for both ArlRS and VraSR TCS as determinants responsible for MW2 survival in the presence of sub-MIC ceftaroline. Subsequent analysis showed that dual disruption of both arlRS and vraSR resulted in a very strong ceftaroline hypersensitivity phenotype. Genetic complementation analysis confirmed these results and fur-ther revealed that arlRS and vraSR likely regulate some common pathway(s) yet to be determined. [...]

VILLANUEVA SAN MARTIN, Maite, et al . The Role of ArlRS and VraSR in Regulating Ceftaroline Hypersusceptibility in Methicillin-Resistant Staphylococcus aureus. Antibiotics , 2021, vol. 10, no. 7, p. 821

DOI : 10.3390/antibiotics10070821 PMID : 34356742

Available at:

http://archive-ouverte.unige.ch/unige:153652

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Supplemental Figure S1. Spot test assay for sub-MIC ceftaroline sensitivity.

S. aureus CA-MRSA strain MW2 and derivatives with disruption in the TCS systems srr or agr, together with MW2 ΔXV, or ΔXIV versions (chromosomally complemented derivatives with the indicated TCS system in parenthesis). The upper panel corresponds to MHA plates containing 0.25 µg/mL of ceftaroline.

Lower panel correspond to MHA plates without ceftaroline. Spot serial

dilutions are indicated at the left margin. The first spot (10 µL) corresponds to

1.5 x 10

colony forming units (CFU). Note that disruption of neither srr nor agr

results in a detectable change in viable colony counts at this sub-MIC

ceftaroline concentration for these strains (MIC 0.5 μg/mL). Similarly, the

restoration by chromosomal complementation of either srr or agr TCS system

in the MW2 ΔXV strain does not detectably restore growth of the ΔXV strain,

which is hypersensitive to ceftaroline in this condition.