Computer-aided design for improved lantibiotics

Information

  • Research Project
  • 10138754
  • ApplicationId
    10138754
  • Core Project Number
    R41GM136034
  • Full Project Number
    1R41GM136034-01A1
  • Serial Number
    136034
  • FOA Number
    PA-19-270
  • Sub Project Id
  • Project Start Date
    8/1/2021 - 3 years ago
  • Project End Date
    7/31/2022 - 2 years ago
  • Program Officer Name
    LYSTER, PETER
  • Budget Start Date
    8/1/2021 - 3 years ago
  • Budget End Date
    7/31/2022 - 2 years ago
  • Fiscal Year
    2021
  • Support Year
    01
  • Suffix
    A1
  • Award Notice Date
    7/30/2021 - 3 years ago
Organizations

Computer-aided design for improved lantibiotics

ABSRACT With the ever-increasing problem of antibiotic resistance and the concurrent use of antibiotics in the food chain and in agriculture, there is an urgent and unmet need for new classes of antibiotics. Lantibiotics represent a large untapped pipeline of attractive scaffolds for the development of novel antibiotics. Previous in vitro and in vivo studies support the concept that lantibiotics are efficacious in Gram-positive models of infection, and that they are safe. Mutacin 1140 (MU1140) is a lantibiotic discovered by Oragenics, which has received considerable attention as a potentially novel antimicrobial agent because of its spectrum of activity, potency, low frequency of antimicrobial resistance, limited cytotoxicity, and overall pharmacological profile. MU1140 is an attractive scaffold for future antibiotic engineering by virtue of its excellent safety profile, novel Mechanism of Action, and the bacteria?s limited ability to develop resistance once it will be used in the clinic. In the proposed research, we will investigate in silico the interaction between MU1140 and its molecular target, to rank top performers of new analogs of MU1140 using molecular modeling. Those virtually screened compounds will be prioritized based on relevant pharmacologic properties. Lead compounds from computer modeling will be synthesized in the laboratory, purified, and characterized to confirm their solubility and stability in human serum, and that the substitution/modification did not negatively impact the potency of the analogs, as compared to MU1140. By the end of the proposed Phase 1 project, we will have confirmed the critical characteristics of synthetic analogs designed in silico, which will provide a solid framework for future development. This application is a joint effort between PI Park and Dr. Handfield at Oragenics, and their collaborators from Florida International University, Profs. Gerstman and Chapagain. Investigators will work closely together to implement the goals of the project and ensure the aims and tasks are performed in a timely manner.

IC Name
NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
  • Activity
    R41
  • Administering IC
    GM
  • Application Type
    1
  • Direct Cost Amount
  • Indirect Cost Amount
  • Total Cost
    256654
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    859
  • Ed Inst. Type
  • Funding ICs
    NIGMS:256654\
  • Funding Mechanism
    SBIR-STTR RPGs
  • Study Section
    ZRG1
  • Study Section Name
    Special Emphasis Panel
  • Organization Name
    ORAGENICS, INC.
  • Organization Department
  • Organization DUNS
    039073601
  • Organization City
    ALACHUA
  • Organization State
    FL
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    326159496
  • Organization District
    UNITED STATES