PYED-1 Overcomes Colistin Resistance in Acinetobacter baumannii

Abstract

Antibiotic resistance has become more and more widespread over the recent decades, becoming a major global health problem and causing colistin to be increasingly used as an antibiotic of last resort. Acinetobacter baumannii, an opportunistic pathogen that has rapidly evolved into a superbug exhibiting multidrug-resistant phenotypes, is responsible for a large number of hospital infection outbreaks. With the intensive use of colistin, A. baumannii resistance to colistin has been found to increase significantly. In previous work, we identified a deflazacort derivative, PYED-1 (pregnadiene-11-hydroxy-16,17-epoxy-3,20-dione-1), which exhibits either direct-acting or synergistic activity against Gram-positive and Gram-negative species and Candida spp., including A. baumannii. The aim of this study was to evaluate the antibacterial activity of PYED-1 in combination with colistin against both A. baumannii planktonic and sessile cells. Furthermore, the cytotoxicity of PYED-1 with and without colistin was assessed. Our results show that PYED-1 and colistin can act synergistically to produce a strong antimicrobial effect against multidrug-resistant populations of A. baumannii. Interestingly, our data reveal that PYED-1 is able to restore the efficacy of colistin against all colistin-resistant A. baumannii isolates. This drug combination could achieve a much stronger antimicrobial effect than colistin while using a much smaller dosage of the drugs, additionally eliminating the toxicity and resistance issues associated with the use of colistin.

Keywords: antibiofilm molecules; antibiotic adjuvants; corticosteroids; killing kinetics; multidrug-resistant A. baumannii; synergistic activity.

Figure 1

Chemical structure of PYED-1.

Scheme 1

Synthesis of PYED-1.

Figure 2

Time–kill curves of A. baumannii 249 treated with 1 μg/mL colistin (green lines), 16 μg/mL PYED-1 (red lines) or a combination of colistin and PYED-1 at previous concentrations (blue lines). The untreated controls are shown with black lines. Data are mean values from three independent experiments, and error bars represent standard deviations.

Figure 3

Biofilm-formation-inhibition effects of colistin/PYED-1 combination on A. baumannii 249 strain. Data are expressed as the mean ± standard deviation (SD) of three replicates. *** p < 0.001, significance was analyzed by one-way ANOVA.

Figure 4

Effects of PYED-1 and colistin association on erythrocytes. The positive and negative controls were 1% (v/v) Triton X-100 and 1% DMSO solution, respectively. Data are expressed as the mean ± standard deviation (SD) of three replicates. *** p < 0.001, significance was analyzed by one-way ANOVA; ns, not statistically significant.