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Published on: April 18, 2019
1,2,4-Oxadiazole antimicrobials act synergistically with daptomycin and display rapid kill kinetics against MDR
Glen P Carter1,2, Jitendra R Harjani3, Lucy Li2
1Antimicrobial Reference and Research Unit, Microbiological Diagnostic Unit Public Health Laboratory, Department of Microbiology & Immunology, Doherty Institute, The University of Melbourne, Melbourne, Australia.
Background:
Enterococcus faecium is an important nosocomial pathogen. It has a high propensity for horizontal gene transfer, which has resulted in the emergence of MDR strains that are difficult to treat. The most notorious of these, vancomycin-resistant E. faecium, are usually treated with linezolid or daptomycin. Resistance has, however, been reported, meaning that new therapeutics are urgently needed. The 1,2,4-oxadiazoles are a recently discovered family of antimicrobials that are active against Gram-positive pathogens and therefore have therapeutic potential for treating E. faecium. However, only limited data are available on the activity of these antimicrobials against E. faecium.
Objectives:
To determine whether the 1,2,4-oxadiazole antimicrobials are active against MDR and daptomycin-non-susceptible E. faecium.
Methods:
The activity of the 1,2,4-oxadiazole antimicrobials against vancomycin-susceptible, vancomycin-resistant and daptomycin-non-susceptible E. faecium was determined using susceptibility testing, time-kill assays and synergy assays. Toxicity was also evaluated against human cells by XTT and haemolysis assays.
Results:
The 1,2,4-oxadiazoles are active against a range of MDR E. faecium, including isolates that display non-susceptibility to vancomycin and daptomycin. This class of antimicrobial displays rapid bactericidal activity and demonstrates superior killing of E. faecium compared with daptomycin. Finally, the 1,2,4-oxadiazoles act synergistically with daptomycin against E. faecium, with subinhibitory concentrations reducing the MIC of daptomycin for non-susceptible isolates to a level below the clinical breakpoint.
Conclusions:
The 1,2,4-oxadiazoles are active against MDR and daptomycin-non-susceptible E. faecium and hold great promise as future therapeutics for treating infections caused by these difficult-to-treat isolates.
Insights
New 1,2,4-oxadiazole antimicrobials show promise against multidrug-resistant (MDR) Enterococcus faecium, including strains resistant to vancomycin and daptomycin. These compounds exhibit rapid bactericidal activity and synergistic effects with daptomycin, offering hope for treating challenging infections.
Area of Science:
- Microbiology
- Infectious Diseases
- Pharmacology
Background:
- Enterococcus faecium is a significant nosocomial pathogen.
- Multidrug-resistant (MDR) strains, particularly vancomycin-resistant E. faecium, pose treatment challenges.
- Emerging resistance to current therapies like daptomycin necessitates novel antimicrobial agents.
Purpose of the Study:
- To evaluate the efficacy of 1,2,4-oxadiazole antimicrobials against MDR and daptomycin-non-susceptible Enterococcus faecium.
- To assess the bactericidal activity and synergistic potential of 1,2,4-oxadiazoles in combination with daptomycin.
Main Methods:
- Susceptibility testing was performed on vancomycin-susceptible, vancomycin-resistant, and daptomycin-non-susceptible E. faecium isolates.
- Time-kill assays and synergy assays were conducted to determine antimicrobial activity.
- Toxicity was assessed using XTT and haemolysis assays on human cells.
Main Results:
- 1,2,4-oxadiazoles demonstrated activity against a broad spectrum of MDR E. faecium, including vancomycin- and daptomycin-non-susceptible strains.
- These compounds exhibited rapid bactericidal activity, outperforming daptomycin in killing E. faecium.
- Synergistic activity was observed between 1,2,4-oxadiazoles and daptomycin, lowering daptomycin's minimum inhibitory concentration (MIC) for resistant isolates.
Conclusions:
- 1,2,4-oxadiazoles are effective against MDR and daptomycin-non-susceptible E. faecium.
- This class of antimicrobials shows significant therapeutic potential for treating infections caused by these difficult-to-treat pathogens.
- Further development of 1,2,4-oxadiazoles could provide a crucial new option for combating resistant E. faecium infections.
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