A Conformationally Constrained Cyclic Acyldepsipeptide Is Highly Effective in Mice Infected with Methicillin-Susceptible and -Resistant Staphylococcus aureus.
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.



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.



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 MRSA experiments, 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.



ADEP B315 is safe and can cure mice that have lethal infections of methicillin-sensitive and -resistant strains of S. aureus.
Infectious Diseases Division, Rhode Island Hospital, Providence, RI, United States of America.|Warren Alpert Medical School of Brown University, Providence, RI, United States of America.
Marios
M
Arvanitis
Infectious Diseases Division, Rhode Island Hospital, Providence, RI, United States of America.|Warren Alpert Medical School of Brown University, Providence, RI, United States of America.
Gang
G
Li
Infectious Diseases Division, Rhode Island Hospital, Providence, RI, United States of America.|Warren Alpert Medical School of Brown University, Providence, RI, United States of America.
De-Dong
DD
Li
Department of Pediatrics, Hasbro Children's Hospital, Brown University Alpert Medical School, Providence, RI, United States of America.
Daniel
D
Cotnoir
Department of Pediatrics, Hasbro Children's Hospital, Brown University Alpert Medical School, Providence, RI, United States of America.
Lisa
L
Ganley-Leal
Department of Chemistry, Brown University, 324 Brook Street, Providence, RI, United States of America.
Daniel W
DW
Carney
Department of Chemistry, Brown University, 324 Brook Street, Providence, RI, United States of America.
Jason K
JK
Sello
Infectious Diseases Division, Rhode Island Hospital, Providence, RI, United States of America.|Warren Alpert Medical School of Brown University, Providence, RI, United States of America.
Eleftherios
E
Mylonakis
D000818:Animals; D005260:Female; D055624:Methicillin-Resistant Staphylococcus aureus / Q000302:isolation & purification*; D051379:Mice; D010456:Peptides, Cyclic / Q000737:chemistry / Q000627:therapeutic use*; D013203:Staphylococcal Infections / Q000188:drug therapy*
D010456:Peptides, Cyclic