start phase I study with lead antibiotic - 200 - 500 Beiträge pro Seite

[User5]

Hallo,

Antibiotic Programme

The Company has identified and filed patents on inhibitors of several metalloenzymes that are essential for the survival of pathogenic bacteria. The most advanced programme is focused on inhibitors of polypeptide deformylase (PDF). In pre-clinical studies that programme`s lead compounds have shown high potency against gram positive bacteria, in particular drug-resistant strains of Streptococcus pneumoniae. The Company aims to initiate clinical studies with the programme`s lead compound in 2002 and talks are in progress with other companies to form an R&D collaboration for this programme.
Next milestones: secure collaboration; start phase I study with lead antibiotic - 2002


Gruss User5

[User5]

Hallo,

Background to antibacterial research programme

The clinical efficacy of many existing antibiotics is now being threatened by the emergence of multidrug resistant pathogens. There is, therefore, an urgent need for compounds that act on novel molecular targets which circumvent the established resistance mechanisms.

British Biotech has over 14 years` experience of working with human metalloenzymes that are associated with diseases such as cancer and inflammation, and has assembled a diverse library of inhibitors of their action. Bacterial genomes also contain a number of metalloenzymes, several of which are essential to survival and represent a significant and under-exploited pool of antibacterial targets. None of the currently licensed antibiotics acts on metalloenzyme targets. Hence the aims of our research programme are twofold: to identify all bacterial metalloenzymes that are essential for growth and pathogenicity, and to develop inhibitors of these enzymes as antibacterial drugs.

Underpinning our strategy is a targeted library of metalloenzyme inhibitors (MEIL), which enables efficient identification of potent compounds as the basis for medicinal chemistry programmes. British Biotech uses structure-based design in its medicinal chemistry programmes to drive the creation of improved lead molecules. Bioinformatics has been used to identify metalloenzymes in bacterial genome databases based on conserved metal binding motifs and/or sequence similarity to known metalloenzymes. These potential targets are then validated by genetic knockout studies. Using this strategy a number of antibacterial metalloenzyme targets have been identified and prioritised. A brief summary of our most advanced programmes is provided below.

Peptide Deformylase Inhibitors

Bacterial polypeptide deformylase (PDF) is now widely recognised as an attractive target for antibacterial chemotherapy (Giglione et al 2001 Mol. Microbiol., 36, 1197-205).
> Deformylation is a crucial step in bacterial protein biosynthesis
> PDF is essential for bacterial growth
> The gene encoding PDF (def) is present in all sequenced pathogenic bacterial genomes
> PDF is a new class of metalloenzyme related to the metallo-proteinase superfamily

Figure 1: the methionine cycle for bacterial polypeptide synthesis

Following a screen of British Biotech`s library of metalloenzyme inhibitors we identified novel compounds that were potent and selective inhibitors of PDF and which inhibited the growth of several clinically relevant bacterial pathogens. Many of these compounds were well absorbed following oral administration and were effective in animal models of infection (Clements et al., 2001, Antimicrobial Agents and Chemotherapy, 45, 563-570). A structure-based medicinal chemistry programme was initiated and has produced novel antibiotic compounds with microbiological profiles that suggest the potential to treat in respiratory tract and serious gram-positive infections.

Profile of British Biotech`s PDF inhibitors

> Microbiological activity profile suitable for respiratory tract pathogens
> Resistance frequency similar to fluoroquinolones vs key respiratory tract pathogens
> Demonstrated in vivo potency against antibiotic resistant organisms
> Potential for i.v./oral switch


Bacterial Species
(n =) MIC (mg/ml)
PDFI-1 PDFI-2 PDFI-3 PDFI-4 PDFI-5 PDFI-6
Streptococcus pneumoniae (6) 0.125-0.25 0.125-0.5 <0.125 <0.125 <0.125 0.25-0.5
Haemophilus influenzae (4) 0.5-16 0.25-2 0.5-8 0.5-8 0.5-8 0.25-2
Moraxella catarrhalis (3) <0.125 <0.125 <0.125 <0.125 <0.125 <0.125
Staphylococcus aureus (1) 4 1 2 1 1 1

Table 1: illustrative antibacterial activity of lead PDFIs against respiratory tract pathogens


Strain
(n=) MIC (mg/ml)
PDFI-1 Cipro Moxi Sparflo Trova Norflo
Wild type 0.06 1 0.125 0.5 0.125 8
ParC, gyrA 0.125 32 4 16 8 128

Table 2: comparison of the activity of PDFI vs a range of fluoroquinolones against a Streptococcus pneumoniae (parC, gyrA ) strain.

LpxC inhibitors

Lipid A is the hydrophobic anchor of lipopolysaccharide (LPS), the major lipid component of the outer membrane of gram-negative bacteria. Lipid A is required for bacterial growth and virulence, and inhibition of its biosynthesis is lethal to bacteria. Inhibitors of UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC), a metalloenzyme that catalyses the second step in the biosynthesis of lipid A, have previously been shown to have antibiotic activity (Onishi, et al 1996. Science, 274:980-982). We have identified potent LpxC inhibitors by screening the metalloenzyme inhibitor library against bacteria and the purified enzyme.

> Potent bactericidal gram-negative activity
> Preliminary SAR has been obtained
> Medicinal chemistry programme underway to identify a lead compound.

Gram-positive selective inhibitors

A novel series of compounds with the potential to treat serious Gram-positive infections has been identified as a result of our metalloenzyme screening programme.

> Potent gram-positive activity against Staphylococcus eg. MRSA and Enterococcus eg. VRE
> Bactericidal mode of action
> Emerging SAR
> Low resistance frequency in Staphylococcus
> Initial mechanism of action studies have identified the target pathway
> Medicinal chemistry programme underway to identify a lead compound.

[aekschonaer]

@user 5
hey ami, hast du kein deutsch in der schule gelernt?