A conformationally constrained cyclic acyldepsipeptide is highly effective in mice infected with methicillin-susceptible and -resistant staphylococcus aureus

Marios Arvanitis, Gang Li, De Dong Li, Daniel Cotnoir, Lisa Ganley-Leal, Daniel W. Carney, Jason K. Sello, Eleftherios Mylonakis

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Cyclic acyldepsipeptides (ADEPs) are a novel class of antibacterial agents, some of which (e.g., ADEP 4) are highly active against Gram-positive bacteria. The focus of these in vivo studies is ADEP B315, a rationally designed compound that has the most potent in vitro activity of any ADEP analog reported to date. Methods In vivo efficacy experiments were performed using lethal intraperitoneal mice infection models with a methicillin-sensitive S. aureus (MSSA) and a methicillin-resistant (MRSA) strain. The infected mice were treated with ADEP B315, a des-methyl analog of ADEP 4, vancomycin, or the vehicle used for the ADEPs and their survival was assessed daily. A subset of MSSA-infected mice was sacrificed soon after inoculation and the bacterial burden was measured in their livers and spleens. The toxicity of ADEP B315 was assessed in viability assays using human whole blood cultures. Results In the MSSA experiments, all mice treated with the vehicle succumbed to the infection within 24 hours. All tested compounds were effective in prolonging survival of infected mice (p<0.001). Mice treated with ADEP B315 had a 39% survival rate by 10 days compared to 7% survival in mice treated with a des-methyl ADEP 4 analog (p = 0.017). Survival of the infected mice treated with ADEP B315 was comparable to those treated with vanocmycin (p = 0.12) at the same dose. Further, bacterial burden in the liver and spleen was significantly lower in mice treated with ADEP B315 compared to controls. In the MRSAexperiments, ADEP B315 was able to significantly prolong survival compared to mice treated with either the vehicle (p = 0.001) or vancomycin (p = 0.007). ADEP B315 exhibited no significant toxicity in human whole blood cultures at concentrations up to 25 μg/ml. Conclusions ADEP B315 is safe and can cure mice that have lethal infections of methicillin-sensitive and -resistant strains of S. aureus.

Original languageEnglish (US)
Article numbere0153912
JournalPLoS ONE
Volume11
Issue number4
DOIs
StatePublished - Apr 2016

ASJC Scopus subject areas

  • General

Fingerprint

Dive into the research topics of 'A conformationally constrained cyclic acyldepsipeptide is highly effective in mice infected with methicillin-susceptible and -resistant staphylococcus aureus'. Together they form a unique fingerprint.

Cite this