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THE TECH TRANSFER UNIT
COPENHAGEN UNIVERSITY
Licensee offer
New synthetic antibiotics
against MRSAs: Piperazine
Inhibitors of Bacterial Gyrase
and Topoisomerase IV
The Opportunity
The University of Copenhagen, the Danish Technical University and LEO Pharma A/S
are seeking an industrial partner for an invention related to a novel class of antibiotic
compounds that are effective against methicillin-resistant Staphylococcus aureus
(MRSA).
We offer access to a new class of synthetic antibiotics that target bacterial type II
topoisomerase with a novel mode of action. There are several advantages of
topoisomerase inhibitors as antibiotics. Bacteria contain the two type IIA
topoisomerases DNA gyrase (topoisomerase II) and topoisomerase IV. The active
sites show a high degree of similarity, thus one antibiotic can potentially target those
two distinct enzymes. Consequently, development of resistance would require
mutations in both of the corresponding genes (gyrA for gyrase and parC for
topoisomerase IV).
The problem
The extensive use of penicillin derivatives has resulted in development in resistance
among bacteria such as MRSA. The mortality rate for humans infected is 15-60% and
in Europe 25,000 people die every year from infections caused by multidrug-resistant
bacteria. MRSA strains are resistant to the β-lactam antibiotics (penicillins), but
resistance to tetracyclins, macrolides, lincosamides, aminoglycosides, trimethoprim,
and in some cases also to fluoroquinolones is frequently observed. Vancomycin has
for a long time been the drug of last resort to MRSA infections, but this has now
resulted in increasing vancomycin-resistance among MRSA. Therefore, there is a
huge medical need for antibiotics with novel modes of action and a slow kinetics with
respect to development of resistance.
The Invention/technology
The new class of antibiotics is constituted by a piperazine core that links to a
fluoroquinoline and a hydrophobic moiety. The antibiotics target bacterial type II
topoisomerase with mode of action, which is distinct from the one of currently
approved drugs. The antibiotics inhibit bacterial gyrase and topoisomerase IV and
hamper DNA transcription and replication in living bacterial cells.
Key Selling points
One antibiotic can potentially target two different type IIA topoisomerases found in
bacteria. Consequently, development of resistance would require mutations to occur in
both of the corresponding genes (gyrA and parC).
DNA gyrase is not found in humans, and the human topoisomerases have distinct
differences from the bacterial counterparts and are generally not affected by bacterial
topoisomerase inhibitors.
This new class of antibiotics possesses a simple chemical structure, which facilitates
its rapid non costly preparation via chemical synthesis.
Development status
We have a number of promising lead compounds and have performed some lead
optimization and are now approaching preclinical testing of these leads. Date included
show biologic evaluation in enzymatic assays benchmarked with Ciprofloxacin and
NXL101. NXL101 was a lead compound from Novexel but it was discontinued due to
unfavorable route of synthesis and hERG profile discovered in a Phase I trial.
Ciprofloxacin is a widely used of the second-generation quinolones antibiotic.
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Biological evaluation of piperazine-based antibiotic agents in enzymatic
assays against S. aureus gyrase and S. aureus topoisomerase IV.
Entry
Compound
S. aureus
a
gyrase
IC50 (M)
S. aureus
b
topoisomerase IV
IC50 (M)
1
NXL 101
0.34
8.80
2
Ciprofloxacin
3.84
9.16
3
81
0.48
2.47
4
73
0.28
9.92
5
74
0.68
1.81
Our lead compounds have excellent antibiotic properties against MRSA and other
Gram-Positive strains in a similar range as NXL-101 and GSK2140944, a novel
piperidine antibiotic in the pipeline at GSK. Our compounds do not have any antibiotic
activity towards investigated Gram-negative strains. Together with the excellent
antibiotic properties, the compounds of the invention also seem to have suitable
properties with respect to hERG inhibition.
MIC determination by broth microdilution of GSK, NXL-101, our lead compound
and ciprofloxacin against ESKAPE pathogens.
MIC values (ug/ml)
GSK
NXL-101
2140944
Gram positive
UCPH
Cipro-
NCE
floxacin
Staphylococcus aureus
0.8
0.4
0.4
0.4
MRSA, CC398
0.8
0.4
0.4
0.4
Enterococcus faecium
3.1
1.56
1.56
0.1
12.5
>50
>50
0.1
Enterobacter cloacae
50
>50
>50
0.1
Klebsiella pneumoniae
50
>50
>50
0.1
nd
2015 and
Gram negative Pseudomonas aeruginosa
Intellectual property rights
An EP patent application covering the inventions was files on March 2
nd
extended in to a PCT patent application filed on March 2 2016.
Contact information
University of Copenhagen
TechTransfer Office
Universitetsparken 1
2100 Copenhagen
Denmark
Commercial Enquiries:
Peter Stein Nielsen
Commercial Officer
[email protected]
+45 2164 7447 (Mobile)
+45 3533 6447 (Office)
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