Steroid drugs inhibit bacterial respiratory oxidases and are lethal towards methicillin-resistant Staphylococcus aureus

Background: Cytochrome bd complexes are respiratory oxidases found exclusively in prokaryotes that are important during infection for numerous bacterial pathogens.

Methods: In silico docking was employed to screen approved drugs for their ability to bind to the quinol site of Escherichia coli cytochrome bd-I. Respiratory inhibition was assessed with oxygen electrodes using membranes isolated from E. coli and Methicillin-resistant Staphylococcus aureus strains expressing single respiratory oxidases (i.e., cytochromes bd, bo or aa3). Growth/viability assays were used to measure bacteriostatic and bactericidal effects.

Results: The steroid drugs ethinylestradiol and quinestrol inhibited E. coli bd-I activity with IC50 values of 47 ± 28.9 µg/mL (158 ± 97.2 µM) and 0.2 ± 0.04 µg/mL (0.5 ± 0.1 µM), respectively. Quinestrol inhibited growth of an E. coli ‘bd-I only’ strain with an IC50 of 0.06 ± 0.02 µg/mL (0.2 ± 0.07 µM). Growth of a S. aureus ‘bd only’ strain was inhibited by quinestrol with an IC50 of 2.2 ± 0.43 µg/mL (6.0 ± 1.2 µM). Quinestrol exhibited potent bactericidal effects against S. aureus but not E. coli.

Conclusions: Quinestrol inhibits cytochrome bd in E. coli and S. aureus membranes and inhibits the growth of both species yet is only bactericidal towards S. aureus.