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Title: In Vivo and In Vitro Effects of a ClpP-Activating Antibiotic against Vancomycin-Resistant Enterococci

Abstract

ABSTRACT Antibiotics with novel bactericidal mechanisms of action are urgently needed. The antibiotic acyldepsipeptide 4 (ADEP4) activates the ClpP protease and causes cells to self-digest. The effects of ADEP4 and ClpP activation have not been characterized sufficiently for the enterococci, which are important pathogens known for high levels of acquired and intrinsic antibiotic resistance. In the present study, ADEP4 was found to be potently active against bothEnterococcus faecalisandEnterococcus faecium, with MIC 90s of 0.016 μg/ml and 0.031 μg/ml, respectively. ClpP purified fromE. faeciumwas found to bind ADEP4 in a surface plasmon resonance analysis, and ClpP activation by ADEP4 was demonstrated biochemically with a β-casein digestion assay. In addition,E. faeciumClpP was crystallized in the presence of ADEP4, revealing ADEP4 binding to ClpP in the activated state. These results confirm that the anti-enterococcal activity of ADEP4 occurs through ClpP activation. In killing curve assays, ADEP4 was found to be bactericidal against stationary-phase vancomycin-resistantE. faecalis(VRE) strain V583, and resistance development was prevented when ADEP4 was combined with multiple classes of approved antibiotics. ADEP4 in combination with partnering antibiotics also eradicated mature VRE biofilms within 72 h of treatment. Biofilm killing with ADEP4 antibiotic combinations was superior to that with the clinically used combinationsmore » ampicillin-gentamicin and ampicillin-daptomycin. In a murine peritoneal septicemia model, ADEP4 alone was as effective as ampicillin. ADEP4 coadministered with ampicillin was significantly more effective than either drug alone. These data suggest that ClpP-activating antibiotics may be useful for treating enterococcal infections.« less

Authors:
; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
NIHOTHER
OSTI Identifier:
1479031
Resource Type:
Journal Article
Journal Name:
Antimicrobial Agents and Chemotherapy
Additional Journal Information:
Journal Volume: 62; Journal Issue: 8; Journal ID: ISSN 0066-4804
Publisher:
American Society for Microbiology
Country of Publication:
United States
Language:
ENGLISH

Citation Formats

Brown Gandt, Autumn, Griffith, Elizabeth C., Lister, Ida M., Billings, Lisa L., Han, Angel, Tangallapally, Rajendra, Zhao, Ying, Singh, Aman P., Lee, Richard E., and LaFleur, Michael D. In Vivo and In Vitro Effects of a ClpP-Activating Antibiotic against Vancomycin-Resistant Enterococci. United States: N. p., 2018. Web. doi:10.1128/AAC.00424-18.
Brown Gandt, Autumn, Griffith, Elizabeth C., Lister, Ida M., Billings, Lisa L., Han, Angel, Tangallapally, Rajendra, Zhao, Ying, Singh, Aman P., Lee, Richard E., & LaFleur, Michael D. In Vivo and In Vitro Effects of a ClpP-Activating Antibiotic against Vancomycin-Resistant Enterococci. United States. doi:10.1128/AAC.00424-18.
Brown Gandt, Autumn, Griffith, Elizabeth C., Lister, Ida M., Billings, Lisa L., Han, Angel, Tangallapally, Rajendra, Zhao, Ying, Singh, Aman P., Lee, Richard E., and LaFleur, Michael D. Mon . "In Vivo and In Vitro Effects of a ClpP-Activating Antibiotic against Vancomycin-Resistant Enterococci". United States. doi:10.1128/AAC.00424-18.
@article{osti_1479031,
title = {In Vivo and In Vitro Effects of a ClpP-Activating Antibiotic against Vancomycin-Resistant Enterococci},
author = {Brown Gandt, Autumn and Griffith, Elizabeth C. and Lister, Ida M. and Billings, Lisa L. and Han, Angel and Tangallapally, Rajendra and Zhao, Ying and Singh, Aman P. and Lee, Richard E. and LaFleur, Michael D.},
abstractNote = {ABSTRACT Antibiotics with novel bactericidal mechanisms of action are urgently needed. The antibiotic acyldepsipeptide 4 (ADEP4) activates the ClpP protease and causes cells to self-digest. The effects of ADEP4 and ClpP activation have not been characterized sufficiently for the enterococci, which are important pathogens known for high levels of acquired and intrinsic antibiotic resistance. In the present study, ADEP4 was found to be potently active against bothEnterococcus faecalisandEnterococcus faecium, with MIC90s of 0.016 μg/ml and 0.031 μg/ml, respectively. ClpP purified fromE. faeciumwas found to bind ADEP4 in a surface plasmon resonance analysis, and ClpP activation by ADEP4 was demonstrated biochemically with a β-casein digestion assay. In addition,E. faeciumClpP was crystallized in the presence of ADEP4, revealing ADEP4 binding to ClpP in the activated state. These results confirm that the anti-enterococcal activity of ADEP4 occurs through ClpP activation. In killing curve assays, ADEP4 was found to be bactericidal against stationary-phase vancomycin-resistantE. faecalis(VRE) strain V583, and resistance development was prevented when ADEP4 was combined with multiple classes of approved antibiotics. ADEP4 in combination with partnering antibiotics also eradicated mature VRE biofilms within 72 h of treatment. Biofilm killing with ADEP4 antibiotic combinations was superior to that with the clinically used combinations ampicillin-gentamicin and ampicillin-daptomycin. In a murine peritoneal septicemia model, ADEP4 alone was as effective as ampicillin. ADEP4 coadministered with ampicillin was significantly more effective than either drug alone. These data suggest that ClpP-activating antibiotics may be useful for treating enterococcal infections.},
doi = {10.1128/AAC.00424-18},
journal = {Antimicrobial Agents and Chemotherapy},
issn = {0066-4804},
number = 8,
volume = 62,
place = {United States},
year = {2018},
month = {5}
}