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.
Highlights
Hospital-acquired infections represent a major problem in high or upper-middle income countries, with an incidence rate of 5% in the United States and 7.1% in Europe [1]
In the frame of a study devoted to the development of a novel and convenient synthetic strategy for the preparation of DFZ, we recently found that a DFZ synthetic precursor called PYED-1, exhibited a good antibacterial activity against Staphylococcus aureus ATCC 29213 and Acinetobacter baumannii ATCC 17978 without showing cytotoxicity [6]
We extended our initial studies on the antimicrobial activity of this compound, by testing its efficacy against a panel of Gram-negative and Gram-positive pathogens, including S. aureus, Enterococcus spp., A. baumannii, P. aeruginosa, K. pneumoniae, E. coli, and Enterobacter spp
Summary
Hospital-acquired infections represent a major problem in high or upper-middle income countries, with an incidence rate of 5% in the United States and 7.1% in Europe [1]. A family of naturally-occurring secondary metabolites characterized by a four-fused ring structure, have exhibited a wide range of biological activities and have been shown to function as antitumoral, antiviral, antibacterial, and antioxidant agents [4]. The heterocyclic corticosteroid deflazacort (DFZ, Figure 1), an oxazoline-derivative of prednisolone, has been recently approved for the treatment of Duchenne dystrophy [5] showing high efficacy and good tolerability. In the frame of a study devoted to the development of a novel and convenient synthetic strategy for the preparation of DFZ, we recently found that a DFZ synthetic precursor called PYED-1 (pregnadiene-11-hydroxy-16α,17α-epoxy-3,20-dione-1), exhibited a good antibacterial activity against Staphylococcus aureus ATCC 29213 and Acinetobacter baumannii ATCC 17978 without showing cytotoxicity [6]. We demonstrated that PYED-1 has a weak effect against Stenotrophomonas maltophilia clinical isolates but at sub-inhibitory concentrations it inhibits biofilm formation of the reference S. maltophilia K279a strain [7]
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