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More than 100 antibiotic compounds have been discovered since
Alexander Fleming invented penicillin in 1928, but none within the
past 30 years. Now a joint venture between the Defense Threat
Reduction Agency's Joint Science and Technology Office, U.S. Army
Medical Research Institute of Infectious Diseases (USAMRIID), Joint
Program Executive Office (JPEO) and Paratek Pharmaceuticals, a
U.S.-based biopharmaceutical company, is exploring a new class of
tetracycline that could combat biological threats to our
warfighters.
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July 16, 2011 - This image depicts the site of action of some of the major categories of antibiotics. (Photo courtesy of Kendrick Johnson)
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While a new antibiotic is necessary to combat drug resistant
biowarfare pathogens, there are inherent challenges in antibiotic
discovery, such as difficulty in establishing a broad-spectrum
application while avoiding potential toxicity. In addition, in order
to be suitable for warfighter use, new antibiotics must exhibit
superiority or equivalence compared to the current military standard
of care.
Biowarfare pathogens also require special handling
and biosafety precautions, such as Biosafety Level (BSL)- 3
containment and compliance with Food and Drug Administration
requirements for development under the Animal Rule, as clinical
trials in humans are unethical or unfeasible. USAMRIID provides
expertise in both handling biowarfare pathogens and testing
compounds against biowarfare pathogens through animal models.
The group's Core Antibiotic Screening Project, with funding from
JSTO, screens antibacterial compounds against BSL-3 select agents
and identifies which compounds have activity. Within this core
capability, small molecules are screened against a panel of 150
bacterium strains (30 strains per select agent of interest including
B. pseudomallei (melioidosis), B. mallei (glanders), Bacillus
anthracis (anthrax), Yersinia pestis (plague), and Francisella
tularensis (tularemia)) to establish effectiveness against select
agents.
The antibacterial compounds demonstrating good in
vitro efficacy are advanced to in vivo evaluation in biological
warfare agent challenge models. Ultimately, the compounds will
become part of the FDA's Animal Rule studies through the Label
Expansion program. This program assesses whether or not a specific
drug can treat additional types of patients and diseases beyond the
drug's original intended use.
In 2015, the Label Expansion
program yielded FDA approval of a supplemental New Drug Application
for moxifloxacin for the oral and IV treatment and post-exposure
prophylaxis of infection caused by Y. pestis. This success spurred
JSTO and JPEO to provide additional funding, expanding USAMRIID's
Label Expansion program to integrate a pipeline of potential
late-development candidates for repurposing against biowarfare
agents. This approach allows the Department of Defense to reduce the
development cycle for new medical countermeasures while increasing
warfighter safety, supporting efficiency and cost-saving
initiatives.
Omadacycline, a Paratek-developed antibiotic,
is currently under evaluation by USAMRIID's Label Expansion program.
The well-tolerated, once-daily oral and IV antibiotic is the first
in a new class of tetracyclines, known as aminomethylcyclines, with
broad-spectrum activity against gram-positive, gram-negative and
atypical bacteria.
In June 2016, the new antibiotic
demonstrated positive results for efficacy and safety in a Phase 3
clinical study for skin structure infection and acute bacterial
skin. The Phase 3 registration study for community-acquired
bacterial pneumonia comparing IV-to-oral omadacycline to IV-to-oral
moxifloxacin was initiated in November 2015.
Enrollment
figures are on track to report top line data as early as the third
quarter of 2017. The FDA granted omadacycline ‘Qualified Infectious
Disease Product' designation and ‘Fast Track' status. The Animal
Rule studies, performed in collaboration with USAMRIID, are designed
to confirm humanized dosing regimens of omadacycline and establish
the efficacy of omadacycline against biodefense pathogens, including
Yersinia pestis and Bacillus anthracis.
The joint DTRA,
JPEO, USAMRIID and Paratek effort represents a valuable partnership
within the Chemical and Biological Defense Program. The work
highlights continuing efforts to engage industry and reduce
biological threats to our warfighters. The resulting capability will
bolster the military's medical defense toolbox, increasing the
number of options available to combat infections in the event of a
biological attack.
By Dr. Amanda Horstman-Smith
Defense Threat Reduction Agency's
Chemical and Biological Technologies Department
Provided
through DVIDS
Copyright 2017
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