1,2,4-Oxadiazole antimicrobials act synergistically with daptomycin and display rapid kill kinetics against MDR Enterococcus faecium

Carter, Glen P.; Harjani, Jitendra R.; Li, Lucy; Pitcher, Noel P.; Nong, Yi; Riley, Thomas V.; Williamson, Deborah A.; Stinear, Timothy P.; Baell, Jonathan B.; Howden, Benjamin P

doi:10.1093/jac/dky064

Cited by 12 publications

(12 citation statements)

References 21 publications

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“…Our previous findings demonstrated that compound 1 also displayed potent activity against a range of clinically relevant E. faecium strains, including both VREfm and daptomycin-resistant strains. 31 Compound 1 was not toxic against the human cell line HepG2 at the E. faecium MIC 90 (2 μg/mL); however, reduced viability was observed at higher concentrations. This was deemed to represent a potentially narrow therapeutic window, but analogues of compound 1 have been reported by Spink et al in 2015 with activity against S. aureus and reduced toxicity against HepG2 cells.…”

Section: Resultsmentioning

confidence: 89%

“…1 has previously been shown to possess membrane-lytic activity, with concentrations in excess of 64 μg/mL leading to haemolysis in human erythrocytes. 31 To determine whether 15e displayed a similar membrane-lytic activity as 1 , the compound was tested against human erythrocytes as before ( Figure 4 c). Limited haemolysis was observed following incubation of human erythrocytes with 4 μg/mL 15e (approximate MIC of C. difficile and E. faecium ), with only 2.5% (range: 0–7%) of erythrocytes undergoing lysis.…”

Section: Resultsmentioning

confidence: 99%

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Development of 1,2,4-Oxadiazole Antimicrobial Agents to Treat Enteric Pathogens within the Gastrointestinal Tract

et al. 2022

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Colonization of the gastrointestinal (GI) tract with pathogenic bacteria is an important risk factor for the development of certain potentially severe and life-threatening healthcare-associated infections, yet efforts to develop effective decolonization agents have been largely unsuccessful thus far. Herein, we report modification of the 1,2,4-oxadiazole class of antimicrobial compounds with poorly permeable functional groups in order to target bacterial pathogens within the GI tract. We have identified that the quaternary ammonium functionality of analogue 26a results in complete impermeability in Caco-2 cell monolayers while retaining activity against GI pathogens Clostridioides difficile and multidrug-resistant (MDR) Enterococcus faecium . Low compound recovery levels after oral administration in rats were observed, which suggests that the analogues may be susceptible to degradation or metabolism within the gut, highlighting a key area for optimization in future efforts. This study demonstrates that modified analogues of the 1,2,4-oxadiazole class may be potential leads for further development of colon-targeted antimicrobial agents.

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Section: Resultsmentioning

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Development of 1,2,4-Oxadiazole Antimicrobial Agents to Treat Enteric Pathogens within the Gastrointestinal Tract

et al. 2022

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“…Thus, we came up with an idea to examine 1,2,4-oxadiazole ring as an alternative core for the promising 2-imidazoline-containing periphery, as it could provide novel two-heterocycles-hybrid based series of compounds for further diverse biological evaluation. These expectations were supported by several successful series of variously biologically active oxadiazoles synthesized and evaluated in our group [7,8,9,10], as well as by recent example of anti-MRSA (Methicillin-Resistant Staphylococcus aureus ) and anti-VRE (Vancomycin-Resistant Enterococcus ) active antibiotics incorporating 3-phenoxyphenyl-substituted 1,2,4-oxadiazoles, that have been recently reported [11,12,13,14,15,16,17].…”

Section: Introductionmentioning

confidence: 84%

1,2,4-Oxadiazole/2-Imidazoline Hybrids: Multi-target-directed Compounds for the Treatment of Infectious Diseases and Cancer

Shetnev

Baykov

Kalinin

et al. 2019

IJMS

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Replacement of amide moiety with the 1,2,4-oxadiazole core in the scaffold of recently reported efflux pump inhibitors afforded a novel series of oxadiazole/2-imidazoline hybrids. The latter compounds exhibited promising antibacterial activity on both Gram-positive (Staphylococcus aureus, Bacillus subtilis) and Gram-negative (Escherichia coli, Pseudomonas fluorescens) strains. Furthermore, selected compounds markedly inhibited the growth of certain drug-resistant bacteria. Additionally, the study revealed the antiproliferative activity of several antibacterial frontrunners against pancreas ductal adenocarcinoma (PANC-1) cell line, as well as their type-selective monoamine oxidase (MAO) inhibitory profile.

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“…Animal experimentation was carried out with approval from the University of Melbourne, Department of Biochemistry and Molecular Biology, Dental Science, Medicine, Microbiology & Immunology, and Surgery Animal Ethics Committee. A total of 6–8 weeks old female C57BL/6 mice were infected with either the daptomycin-susceptible strain DMG1800332, or daptomycin-resistant clinical isolates DMG1901766, DMG1700661 ( Carter et al, 2018 ), or DMG1700787. Mice were infected via intraperitoneal injection with 10 9 CFU resuspended in sterile rat faecal extract (SRFE) ( Singh et al, 1998 ).…”

Section: Methodsmentioning

confidence: 99%

Daptomycin Resistance Occurs Predominantly in vanA-Type Vancomycin-Resistant Enterococcus faecium in Australasia and Is Associated With Heterogeneous and Novel Mutations

Higgs

Turner

et al. 2021

Front. Microbiol.

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Healthcare associated infections caused by vancomycin-resistant Enterococcus faecium (VREfm) have a major impact on health outcomes. VREfm is difficult to treat because of intrinsic and acquired resistance to many clinically used antimicrobials, with daptomycin being one of the few last line therapeutic options for treating multidrug-resistant VREfm. The emergence of daptomycin-resistant VREfm is therefore of serious clinical concern. Despite this, the impact that daptomycin-resistant VREfm have on patient health outcomes is not clearly defined and knowledge on the mechanisms and genetic signatures linked with daptomycin resistance in VREfm remains incomplete. To address these knowledge gaps, phenotypic daptomycin susceptibility testing was undertaken on 324 E. faecium isolates from Australia and New Zealand. Approximately 15% of study isolates were phenotypically resistant to daptomycin. Whole genome sequencing revealed a strong association between vanA-VREfm and daptomycin resistance, with 95% of daptomycin-resistant study isolates harbouring vanA. Genomic analyses showed that daptomycin-resistant VREfm isolates were polyclonal and carried several previously characterised mutations in the liaR and liaS genes as well as several novel mutations within the rpoB, rpoC, and dltC genes. Overall, 70% of daptomycin-resistant study isolates were found to carry mutations within the liaR, rpoB, rpoC, or dltC genes. Finally, in a mouse model of VREfm bacteraemia, infection with the locally dominant daptomycin-resistant clone led to reduced daptomycin treatment efficacy in comparison to daptomycin-susceptible E. faecium. These findings have important implications for ongoing VREfm surveillance activities and the treatment of VREfm infections.

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1,2,4-Oxadiazole antimicrobials act synergistically with daptomycin and display rapid kill kinetics against MDR Enterococcus faecium

Abstract: 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.

Cited by 12 publications

References 21 publications

Development of 1,2,4-Oxadiazole Antimicrobial Agents to Treat Enteric Pathogens within the Gastrointestinal Tract

Development of 1,2,4-Oxadiazole Antimicrobial Agents to Treat Enteric Pathogens within the Gastrointestinal Tract

1,2,4-Oxadiazole/2-Imidazoline Hybrids: Multi-target-directed Compounds for the Treatment of Infectious Diseases and Cancer

Daptomycin Resistance Occurs Predominantly in vanA-Type Vancomycin-Resistant Enterococcus faecium in Australasia and Is Associated With Heterogeneous and Novel Mutations

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