Health Protection Agency

Syntaxin Limited

King's College London

Secretary of State for Health and Social Care

University of Southampton

The Secretary of State for Health

John Mark Sutton

Clifford Charles Shone

Keith Foster

John Andrew Chaddock

Philip Marks

Conrad Padraig Quinn

Patrick Stancombe

Hywel Morgan

Khondaker Mirazur Rahman

Jonathan Wayne

Nigel Silman

Bassam Hallis

Neil David Hammond Raven

Daniel Spencer

Neil D Raven

Mark Benjamin Laws

Kazi Nahar

Charlotte Hind

Pietro Picconi

Shirin Jamshidi

Philip James Alister Skipper

The invention relates to antibiotic compounds of formula (A1) and pharmaceutically acceptable salts, solvates, tautomers and combinations thereof, wherein X and L are optional linkers and one of Ror Rcomprises Ar, wherein Aris an antibiotic resistance breaker moiety which comprises an optionally substituted Caryl, Caralkyl, Cheteroaryl, Cheteroaralkyl, Cheterocyclyl, Cheterocyclalkyl, Ccarbocyclyl, Ccarbocyclalkyl, &#x2014;C(&#x2550;NR')&#x2014;NR&#x2032;R&#x2033; or &#x2014;CH&#x2014;CH&#x2550;CHgroup; wherein after administration of the compound to a bacterial infection this moiety reduces or prevents efflux. The invention also discloses pharmaceutical compositions comprising compounds of formula (A1) and the use of such compounds as medicaments, in particular, to treat bacterial infections, such as drug-resistant bacterial infections.

Antibiotic resistance breakers

The invention relates to pyrrolobenzodiazepines compounds (PBDs) and to pharmaceutically acceptable salts thereof, which are useful as medicaments, in particular, to treat bacterial infections. The PBDs are compounds of formula (I): and salts and solvates thereof; wherein: dotted lines indicates the optional presence of a double bond; X, X, X, Xand Xare connecting functional groups; L is Calkylene; R, Rand Rare independently selected from phenylene, cyclopentanylene, cyclohexanylene, 5- to 9-membered heteroarylene and 5- to 6-membered hetereocyclylene groups, and these groups are optionally substituted with up to three optional substituent groups; Ris selected from N(Calkyl)(Calkyl), 5- to 6-membered nitrogen-containing hetereocyclyl groups, a monosaccharide moiety and an amino monosaccharide moiety wherein these groups are optionally substituted; and Rand Reither together form a double bond, or are selected from H and OR, or Ris a prodrug moiety and Ris OR; m is 0 or 1; with the proviso that when Xis C(O)NH then the up to three optional substituents of Rare not selected from (CH2)-COR; with the proviso that when Xis (CH)O then Ris not phenylene, m is 1 and Ris not a 5- to 9-membered heteroarylene; and with the proviso that when Xis C(O)NH or NHC(O) that Rand/or Ris not 5- to 9-membered heteroarylene. 

PBD antibacterial agents

A single polypeptide is provided which comprises first and second domains. The first domain enables the polypeptide to cleave one or more vesicle or plasma-membrane associated proteins essential to exocytosis, and the second domain enables the polypeptide to be translocated into a target cell or increases the solubility of the polypeptide, or both. The polypeptide thus combines useful properties of a clostridial toxin, such as a botulinum or tetanus toxin, without the toxicity associated with the natural molecule. The polypeptide can also contain a third domain that targets it to a specific cell, rendering the polypeptide useful in inhibition of exocytosis in target cells. Fusion proteins comprising the polypeptide, nucleic acids encoding the polypeptide and methods of making the polypeptide are also provided. Controlled activation of the polypeptide is possible and the polypeptide can be incorporated into vaccines and toxin assays.

Recombinant toxin fragments

A transmissible spongiform encephalopathy (TSE) agent is inactivated by exposing the TSE agent to a thermostable proteolytic enzyme at elevated temperature and at acid or alkaline pH. Following this step, or separately, presence of TSE infectivity is detected by detection of dimers of prion protein.

Degradation and detection of TSE infectivity

A composition for delivery of superoxide dismutase to neuronal cells comprise a superoxide dismutase linked by a linker to a neuronal cell targeting component, which component comprises a first domain that binds to a neuronal cell and a second domain that translocates the superoxide dimutase into the neuronal cell. After translocation, the linker is cleaved to release superoxide dimutase from the neuronal cell targeting domain. Also described is use of the composition for treatment of oxidative damage to neuronal cells and further targeting of the composition using human mitochondrial leader sequences. A hybrid polypeptide is described that contains a bacterial superoxide dismutase plus a sequence that targets a human mitochondira.

Delivery of superoxide dismutase to neuronal cells

A non-toxic polypeptide, for delivery of a therapeutic agent to a neuronal cell, comprises a binding domain that binds to the neuronal cell, and a translocation domain that translocates the therapeutic agent into the neuronal cell, wherein the translocation domain is not a Hdomain of a clostridial toxin and is not a fragment or derivative of a Hdomain of a clostridial toxin.

Constructs for delivery of therapeutic agents to neuronal cells

Growing community of inventors

Salisbury, United Kingdom

John Mark Sutton