AUTHOR=Poshvina Darya V. , Dilbaryan Diana S. , Kasyanov Sergey P. , Sadykova Vera S. , Lapchinskaya Olda A. , Rogozhin Eugene A. , Vasilchenko Alexey S. 

TITLE=Staphylococcus aureus is able to generate resistance to novel lipoglycopeptide antibiotic gausemycin A

JOURNAL=Frontiers in Microbiology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2022.963979

DOI=10.3389/fmicb.2022.963979

ISSN=1664-302X

ABSTRACT=<p>Gausemycin A is the first member of the novel lipoglycopeptides family produced by <italic>Streptomyces roseoflavus</italic> INA-Ac-5812. Gausemycin A has a pronounced bactericidal activity against methicillin-resistant <italic>Staphylococcus aureus</italic>. However, the ability of <italic>S. aureus</italic> to be resistant to gausemycin A has not been investigated yet. Using serial passaging, we have obtained the resistant variant <italic>S. aureus</italic> 5812R, which is 80 times more resistant compared to the parent strain. Susceptibility testing of <italic>S. aureus</italic> 5812R revealed the acquisition of cross-resistance to daptomycin, cefazolin, tetracycline, and gentamicin, while the resistance to vancomycin, nisin, and ramoplanin was absent. Whole genome sequencing revealed single nucleotide polymorphism (SNP) and deletions in <italic>S. aureus</italic> 5812R, among which are genes encoding efflux pump (<italic>sepA</italic>), the two-component Kdp system (<italic>kdpE</italic>), and the component of isoprenoid biosynthesis pathway (<italic>hepT)</italic>. Phenotypically, <italic>S. aureus</italic> 5812R resembles a small-colony variant, as it is slow-growing, forms small colonies, and is deficient in pigments. Profiling of fatty acids (FA) composition constituting the cytoplasmic membrane of <italic>S. aureus</italic> 5812R revealed the prevalence of <italic>anteiso</italic>-branched FA, while straight FA was slightly less present. The evidence also showed that the gausemycin A-resistant strain has increased expression of the <italic>cls2</italic> gene of the cardiolipin synthase. The performed checkerboard assay pointed out that the combination of gausemycin A and ciprofloxacin showed a synergistic effect against <italic>S. aureus</italic> 5812R.</p>