Glen P Carter1,2, Jitendra R Harjani3, Lucy Li2, Noel P Pitcher3, Yi Nong2, Thomas V Riley4,5,6, Deborah A Williamson1,2, Timothy P Stinear2, Jonathan B Baell3,7, Benjamin P Howden1,2. 1. Antimicrobial Reference and Research Unit, Microbiological Diagnostic Unit Public Health Laboratory, Department of Microbiology & Immunology, Doherty Institute, The University of Melbourne, Melbourne, Australia. 2. Department of Microbiology & Immunology, Doherty Institute, The University of Melbourne, Melbourne, Australia. 3. Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia. 4. School of Medical and Health Sciences, Edith Cowan University, Perth, Western Australia, Australia. 5. School of Veterinary and Life Sciences, Murdoch University, Perth, Western Australia, Australia. 6. Department of Microbiology, PathWest Laboratory Medicine, Perth, Western Australia, Australia. 7. School of Pharmaceutical Sciences, Nanjing Tech University, No. 30 South Puzhu Road, Nanjing 211816, People's Republic of China.
Abstract
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.
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.
Authors: Gustavo Henrique Rodrigues Vale de Macedo; Gabrielle Damasceno Evangelista Costa; Elane Rodrigues Oliveira; Glauciane Viera Damasceno; Juliana Silva Pereira Mendonça; Lucas Dos Santos Silva; Vitor Lopes Chagas; José Manuel Noguera Bazán; Amanda Silva Dos Santos Aliança; Rita de Cássia Mendonça de Miranda; Adrielle Zagmignan; Andrea de Souza Monteiro; Luís Cláudio Nascimento da Silva Journal: Pathogens Date: 2021-02-02
Authors: Noel P Pitcher; Jitendra R Harjani; Yichao Zhao; Jianwen Jin; Daniel R Knight; Lucy Li; Papanin Putsathit; Thomas V Riley; Glen P Carter; Jonathan B Baell Journal: ACS Omega Date: 2022-02-18