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

Abstract

Gausemycin A is the first member of the novel lipoglycopeptides family produced by Streptomyces roseoflavus INA-Ac-5812. Gausemycin A has a pronounced bactericidal activity against methicillin-resistant Staphylococcus aureus. However, the ability of S. aureus to be resistant to gausemycin A has not been investigated yet. Using serial passaging, we have obtained the resistant variant S. aureus 5812R, which is 80 times more resistant compared to the parent strain. Susceptibility testing of S. aureus 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 S. aureus 5812R, among which are genes encoding efflux pump (sepA), the two-component Kdp system (kdpE), and the component of isoprenoid biosynthesis pathway (hepT). Phenotypically, S. aureus 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 S. aureus 5812R revealed the prevalence of anteiso-branched FA, while straight FA was slightly less present. The evidence also showed that the gausemycin A-resistant strain has increased expression of the cls2 gene of the cardiolipin synthase. The performed checkerboard assay pointed out that the combination of gausemycin A and ciprofloxacin showed a synergistic effect against S. aureus 5812R.

Gausemycin A-Resistant Staphylococcus aureus Demonstrates Affected Cell Membrane and Cell Wall Homeostasis

“…The molecular mechanisms underlying the development of a gausemycin A-resistant phenotype and cross-resistance to daptomycin are not well understood. In our previous study, after 20 passages, the mutant strain S. aureus GAU-R was characterized by an increase in the MIC of gausemycin A from 2.5 to 200 µg/mL [ 7 ]. In the present study, we aimed to elucidate the mechanism underlying the acquisition of gausemycin A resistance by S. aureus .…”

“…In the late-exponential phase, the expression level of the pgsA gene in the GAU-R strain increased by 8.31-fold, as demonstrated in this study. In our previous work, we also found that the S. aureus GAU-R strain had a slightly more negative relative net charge, as measured with zeta potential, compared to the S. aureus GAU-S strain [ 7 ]. Other studies have reported increased levels of lysyl-PG and decreased levels of PG in daptomycin-resistant isolates [ 36 , 37 ], which sets gausemycin A apart from daptomycin in terms of action.…”

“…The precise mechanism of resistance to gausemycin A is not yet fully understood, although certain features of the resistance phenotype have been identified. Previous research has demonstrated that S. aureus is capable of developing resistance to gausemycin A [ 7 ], which is characterized by an additional reduction in susceptibility to daptomycin [ 7 ]. Further studies are necessary to better understand the resistance profile of gausemycin A and its implications for the treatment of multidrug-resistant Gram-positive infections.…”

Macrolactin A Is an Inhibitor of Protein Biosynthesis in Bacteria

“…McA in twofold serial dilutions as described (Poshvina et al 2022). The cells were incubated at 37°C for 24 h. After incubation, bacterial cells growing at subinhibitory concentrations of McA were used for subsequent passaging.…”

Lipid-Centric Approaches in Combating Infectious Diseases: Antibacterials, Antifungals and Antivirals with Lipid-Associated Mechanisms of Action

“…The latter indicates that reducing the level of negatively charged lipids is not the only strategy for resistance development by changing the membrane properties; the fatty acid profile is also of fundamental importance. For example, the development of resistance of S. aureus to gausemycin A is accompanied by growth in the ratio between the levels of anteisoand iso-BCFA [309]. The membrane fluidity is significantly enhanced when anteiso acyl chains replace iso acyl chains.…”