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Exploratory Chemistry on a new antibiotic

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R44AI122425-01A1
Agency Tracking Number: R44AI122425
Amount: $1,484,593.00
Phase: Phase I
Program: SBIR
Solicitation Topic Code: NIAID
Solicitation Number: PAR14-088
Timeline
Solicitation Year: 2014
Award Year: 2016
Award Start Date (Proposal Award Date): 2016-06-16
Award End Date (Contract End Date): 2019-05-31
Small Business Information
767 CONCORD AVE
Cambridge, MA 02138-1044
United States
DUNS: 140692976
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 DALLAS HUGHES
 (617) 864-2880
 dhughes@novobiotic.com
Business Contact
 ARAM SALZMAN
Phone: (617) 864-2880
Email: asalzman@novobiotic.com
Research Institution
N/A
Abstract

This project studies the structure activity relationship SAR of the newly discovered antibiotic
teixobactin with the goal of delivering a candidate that has development advantages over the parent
compound Teixobactin is an unusual depsipeptide that is the first member of a novel class of peptidoglycan
synthesis inhibitors Teixobactin targets lipid II peptidoglycan precursor and lipid III teichoic acid precursor It
binds to undecaprenyl PP sugars which are not known to be modified as opposed to a later lipid II d ala d ala
modifiable form targeted by vancomycin This unique mode of action binding to two targets neither of which is
a protein suggests that resistance will be very difficult to develop To date no resistance has been detected
Teixobactin has potent activity against a broad range of Gram positive bacteria S aureus MRSA S
pneumoniae B anthracis M tuberculosis E faecalis and E faecium It is active against resistant forms of
these pathogens including vancomycin resistant enterococci Teixobactin was highly efficacious in a murine
MRSA septicemia and thigh infection models and against S pneumoniae in a lung infection model
Teixobactin itself is moving into development However studies of teixobactin have identified a
property of the compound that can be improved Teixobactin has a tendency to gelate in serum which may
present a problem depending on the dosing regimen required for humans e g if higher serum concentrations
of the drug are required for humans than mice and has presented a challenge in administering the compound
at higher doses in preclinical studies Gelation of small peptides is a well known phenomenon that has been
successfully addressed with medicinal chemistry optimization We will conduct a medicinal chemistry campaign
to gain a good understanding of the SAR of the molecule and use this information to produce analogs that do
not gelate but retain potent antibacterial properties Early proactive understanding of the SAR of teixobactin
would also guide the design of new analogs that could address additional issues that may come up during the
development of teixobactin itself
An evaluation of the effect of modifying a variety of positions in the molecule will be conducted
through both semisynthetic and fully synthetic approaches Several analogs have already been produced by
both approaches which demonstrate the feasibility of the approach Multiple analogs will be produced and
tested for antibacterial activity lipid II binding gelation and in vitro ADMET properties Three analogs with
reduced gelation but favorable in vitro properties will be selected for mouse studies including MTD PK and
efficacy against MRSA in the thigh infection model The results of this project will produce a therapeutic lead
candidate ready to enter further development including IND enabling studies Narrative
New antibiotics are needed to combat an impending public health disaster that annually causes
million illnesses in the United States alone The proposed study focuses on understanding the
structure activity relationship of a newly discovered antibiotic with the goal of developing an
antibiotic against multidrug resistant infections

* Information listed above is at the time of submission. *

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