NABATIVI - Novel Approaches to Bacterial Target Identification, Validation and Inhibition

Summary:

Despite the advent of the antibiotic era, infectious diseases retain a prominent position as a major worldwide cause of morbidity and mortality. This problem has worsened with the emergence of multi-antibiotic resistant bacteria and the failure of pharmaceutical company drug discovery programmes to design antibiotics with truly novel modes of action. NABATIVI has put together a unique consortium made of six academic institutions and three highly recognized SMEs with complementary expertise in the fields of molecular pathogenicity and high competitiveness in drug discovery, optimisation and preclinical development. The consortium has been specifically designed to generate new strategies leading to the identification and validation of novel targets for antimicrobials using as model organisms the gram-negatives Pseudomonas aeruginosa and Burkholderia cenocepacia as they cause high morbidity and mortality worldwide. The versatility of these model bacteria will enable the results obtained to be extrapolated to other important bacterial pathogens. The extensive involvement of SMEs in this consortium will enable the selection of lead compounds against the identified targets from their large libraries of natural and synthetic chemicals which, after validation, will establish the basis for the development of new classes of antibacterial drugs. This will result in a reduction in the incidence of diseases caused by these organisms with a direct positive impact on the quality of life and the life expectancy of the higher risk patient populations.

Problem:

The considerable difficulty to resolve P. aeruginosa infections and those caused by other gram-negative pathogens such as B. cenocepacia is thought to reflect the world-wide increasing occurence of antibiotic resistant strains. To combat infections various classes of potent anti-microbial drugs have been developed in the past 80 years, which have considerably improved the management of infectious diseases. This “golden age” of antibiotics engendered such optimism that it was commonly thought bacterial infections would be rapidly eliminated as a cause of mortality. Unfortunately, bacterial resistance to all classes of antibiotics soon appeared. Heavy antibiotic use and person-to-person spread of bacteria have greatly increased antibiotic resistance, and this problem is continually increasing in severity

Results:

To maximise achievements, NABATIVI will generate two alternative types of antibacterials that may escape the extensive mechanisms of bacterial resistance These are: i) conventional antibacterials as far as their chemical features and direct effects on their targets, but novel in terms of mechanism of action and ii) non-conventional antibacterials, such as antisense oligomers, which prevalently act on the expression of the target and not on its function.

The combined efforts are expected to result in a panel of new drugs for the treatment of P. aeruginosa infections in patients with cystic fibrosis and other high-risk patient groups. Furthermore, the knowledge generated will facilitate identification of new targets for the development of anti-microbial drugs in other bacterial pathogens, especially other gram-negative bacteria, such as B. cenocepacia.

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