Steroid Derivatives as Potential Antimicrobial Agents against Staphylococcus aureus Planktonic Cells

Abstract

In this work, the antibacterial activity of deflazacort and several of its synthetic precursors was tested against a panel of bacterial pathogens responsible for most drug-resistant infections including Staphylococcus aureus, Enterococcus spp., Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, and Enterobacter spp. The derivative of deflazacort, PYED-1 (pregnadiene-11-hydroxy-16α,17α-epoxy-3,20-dione-1) showed the best antibacterial activity in a dose-dependent way. We focused on the action of PYED-1 against S. aureus cells. PYED-1 exhibited an additive antimicrobial effect with gentamicin and oxacillin against the methicillin-resistant S. aureus isolate 00717. In addition to its antimicrobial effect, PYED-1 was found to repress the expression of several virulence factors of S. aureus, including toxins encoded by the hla (alpha-haemolysin), hlb (beta-haemolysin), lukE-D (leucotoxins E-D), and sea (staphylococcal enterotoxin A) genes, and cell surface factors (fnbB (fibronectin-binding protein B) and capC (capsule biosynthesis protein C)). The expression levels of autolysin isaA (immunodominant staphylococcal antigen) were also increased.

PYED-1 Inhibits Biofilm Formation and Disrupts the Preformed Biofilm of Staphylococcus aureus

“…The transcriptional levels of isaA (immunodominant staphylococcal antigen) were also markedly (12-fold) reduced (Table 1 and Figure 3). In contrast, the transcriptional levels of isaA were increased by PYED-1 in planktonic cells [11]. Changes in the transcriptional control of isaA in planktonic cells and preformed biofilms were also observed when treating planktonic and biofilm cells with secalonic acid D [31].…”

“…Our previous data showed that PYED-1 inhibition of S. aureus biofilm formation is associated with reduced expression of several genes involved in S. aureus virulence [11]. Here, we investigated the molecular mechanism responsible for the eradication activity of PYED-1.…”

“…Previous studies have shown that higher doses of topical corticosteroids (budesonide, mometasone, and fluticasone), commonly used in the treatment of chronic rhinosinusitis, have effective antibiofilm activity against S. aureus [15]. Recent studies have shown that PYED-1 at 16 g/mL exerts effective inhibitory activity of planktonic cell growth against S. aureus ATCC 29213 [10,11].…”

“…The chemical synthesis and structural characterization of PYED-1 was realized as previously reported [10,11]. PYED-1 was dissolved in dimethyl sulfoxide (DMSO) to the concentration of 50 mg/mL.…”

“…As a result of this, there is an urgent need to develop new agents that inhibit S. aureus biofilm formation, and/or disrupt established biofilms [9]. In previous studies, we showed that pregnadiene-11-hydroxy-16α,17α-epoxy-3,20-dione-1 (PYED-1) exhibits effective antibacterial activity against S. aureus ATCC 29213 and A. baumannii ATCC 17978, without cytotoxic effects [10,11]. Additionally, we demonstrated that PYED-1 at sub-inhibitory concentrations hinders the biofilm formation of the Stenotrophomonas maltophilia K279a strain [12].…”