Download Novel DNA Supercoiling Inhibitors

Novel DNA Supercoiling Inhibitors
for the treatment of drug-resistant bacterial infections
Opportunity
Attributes of antibacterial assets
Following a strategic decision to focus on clinical
stage programs, Biota is seeking to divest its
research stage antibacterial assets
The assets include a preclinical candidate for drug
resistant Gram-positive infections, including MRSA,
and an advanced lead for Gram-negative infections
Biota is open to a range of deal structures including
sale of the assets, with or without Oxford-based
facilities, out-licensing and spin-outs
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In Vivo Efficacy of Preclinical Candidate for
Gram-Positive Infections
S. pneumoniae murine
lung infection model
100
9
8
80
mouse
rat
7
Control
10 mg/kg oral
30 mg/kg oral
100 mg/kg oral
Percent survival
Mean log10 CFU
6 hrs (mouse) or 12 hrs (rat) post dose
S. aureus rodent thigh
infection model
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60
6
\
5

40
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Novel class of small-molecule antibacterials
Dual-targeting of the clinically unexploited
GyrB and ParE subunits of DNA gyrase and
topoisomerase IV
No pre-existing resistance in contemporary
clinical isolates
A low resistance frequency and low propensity
for the development of resistance
Bactericidal activity against a broad range of
bacteria
Active against drug-resistant strains of Grampositive and Gram-negative species
Good bioavailability with potential for
intravenous and oral administration
Efficacious in multiple rodent models of Grampositive and Gram-negative infections
Chemically tractable and scalable synthetic
routes, with an attractive safety profile
Comprehensive patent estate covering major
commercial markets, solely owned by Biota
Long potential period of market exclusivity
20
4
0
3
0
Control 30 mg/kg IV
1
2
3
4
5
Days
In Vivo Efficacy of Lead Compound for
Gram-Negative Infections
6
7
Mechanism of action: Dual-targeting of
DNA gyrase and topoisomerase IV
Inhibition of ATPase activity prevents DNA
supercoiling and decatenation. This is a distinct
mechanism of action from the fluoroquinolones
E. coli NDM-1 septicemia murine survival model
100
ATPase binding
GyrB/ParE
Biota
Percent survival
80
Control
1x 100 mg/kg (1 hr) IV
2x 100 mg/kg (1+3 hrs) IV
60
40
20
1
2
3
Days
4
5
DNA binding
GyrA/ParC
Fluoroquinolones
For detailed information, please contact:
Dr Kate Moore, Senior Director
[email protected]
+44 1865 332713 or +44 7960 508429