Ureadepsipeptides as ClpP Activators

Griffith, Elizabeth C.; Zhao, Ying; Singh, Aman P.; Conlon, Brian P.; Tangallapally, Rajendra; Shadrick, William R.; Liu, Jiuyu; Wallace, Miranda J.; Yang, Lei; Elmore, John M.; Li, Yong; Zheng, Zhong; Miller, Darcie J.; Cheramie, Martin N.; Lee, Robin B.; LaFleur, Michael D.; Lewis, Kim; Lee, Richard E.

doi:10.1021/acsinfecdis.9b00245

Ureadepsipeptides as ClpP Activators

Journal Article · Mon Oct 07 00:00:00 EDT 2019 · ACS Infectious Diseases

DOI:https://doi.org/10.1021/acsinfecdis.9b00245· OSTI ID:1575009

Griffith, Elizabeth C. ^[1]; Zhao, Ying ^[1]; Singh, Aman P. ^[1]; Conlon, Brian P. ^[2]; Tangallapally, Rajendra ^[1]; Shadrick, William R. ^[1]; Liu, Jiuyu ^[1]; Wallace, Miranda J. ^[1]; Yang, Lei ^[1]; Elmore, John M. ^[1]; Li, Yong ^[1]; Zheng, Zhong ^[1]; Miller, Darcie J. ^[1]; Cheramie, Martin N. ^[1]; Lee, Robin B. ^[1]; LaFleur, Michael D. ^[3]; Lewis, Kim ^[2]; ^[1]

St. Jude Children’s Research Hospital, Memphis, TN (United States)
Northeastern Univ., Boston, MA (United States)
Arietis Pharma, Boston, MA (United States)

Acyldepsipeptides are a unique class of antibiotics that act via allosterically dysregulated activation of the bacterial caseinolytic protease (ClpP). The ability of ClpP activators to kill nongrowing bacteria represents a new opportunity to combat deep-seated biofilm infections. However, the acyldepsipeptide scaffold is subject to rapid metabolism. In this study, we explore alteration of the potentially metabolically reactive α,β unsaturated acyl chain. Through targeted synthesis, a new class of phenyl urea substituted depsipeptide ClpP activators with improved metabolic stability is described. The ureadepsipeptides are potent activators of Staphylococcus aureus ClpP and show activity against Gram-positive bacteria, including S. aureus biofilms. These studies demonstrate that a phenyl urea motif can successfully mimic the double bond, maintaining potency equivalent to acyldepsipeptides but with decreased metabolic liability. Although removal of the double bond from acyldepsipeptides generally has a significant negative impact on potency, structural studies revealed that the phenyl ureadepsipeptides can retain potency through the formation of a third hydrogen bond between the urea and the key Tyr63 residue in the ClpP activation domain. Ureadepsipeptides represent a new class of ClpP activators with improved drug-like properties, potent antibacterial activity, and the tractability to be further optimized.

View Accepted Manuscript (DOE)

Research Organization:: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: W-31109-ENG-38

OSTI ID:: 1575009

Journal Information:: ACS Infectious Diseases, Journal Name: ACS Infectious Diseases Journal Issue: 11 Vol. 5; ISSN 2373-8227

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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60 APPLIED LIFE SCIENCES
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acyldepsipeptide
antibiotic
biofilm
ureadepsipeptide

Ureadepsipeptides as ClpP Activators

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