NABATIVI

"Novel Approaches to Bacterial Target Identification, Validation and Inhibition"

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 Obiettivo del progetto (Objective)

'Despite the advent of the antibiotic era, infectious diseases retain their pre-eminent position as major worldwide causes of morbidity and mortality. This problem has been worsen by 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 insitutions and three highly recognized SMEs with complementary expertise in the fields of molecular pathogenicity and broad expertise in drug discovery, optimisation, 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 are key agents of morbidity and mortality worldwide in a wide range of diseases. The versatility of these model bacteria will enable the results obtained to be extrapolated to other 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 and improvement of the treatment of infections caused by these organisms with a direct impact on the quality of life and the life expectancy of the affected risk patient populations.'

Introduzione (Teaser)

Infectious diseases caused by opportunistic pathogens such as Pseudomonas aeruginosa, continue to be a serious cause of morbidity worldwide. The emerging antibiotic resistance is only exacerbating the situation, necessitating the development of antibiotics with truly novel modes of action.

Descrizione progetto (Article)

Over the past forty years, the antibiotics that have entered the market represent mere modifications of existing molecules. To address antimicrobial drug resistance, the EU-funded ?Novel approaches to bacterial target identification, validation and inhibition? (http://www.nabativi.org (NABATIVI)) project was initiated. Researchers worked on selecting lead compounds for future development of a new class of antibiotics to treat infections caused by resistant P. aeruginosa strains.

To identify and validate novel drug targets, scientists screened P. aeruginosa genome and identified essential and virulence targets (genes) as candidates for the development of antibacterials. Targeted mutagenesis experiments and validation in cell and animal models helped identify virulence genes and factors implicated in infection. Interestingly, some targets were found to play key roles in regulating cellular processes linked to P. aeruginosa pathogenesis. The clinical relevance of some of these genes was verified through genome sequencing across a panel of different bacterial isolates. Furthermore, comparative analysis with additional bacterial species resulted in a panel of targets with a global relevance.

For the selection of compounds with antibacterial activity, researchers screened natural products and chemical libraries against specifically selected targets. They also developed novel inhibitors using peptide nucleic acid delivery. A number of extracts and molecules have been found to inhibit some of these targets.

Natural antimicrobial peptide protegrin I was found to bind to the outer membrane protein and interfere with membrane biosynthesis. One attractive protegrin I homologue after toxicity evaluation and in vivo efficacy studies, was envisaged for pulmonary administration as a possible therapeutic approach. This compound is currently being developed and commercialised to treat patients suffering from P. aeruginosa infections.

Given that nearly two thirds of the hospital-associated infections could be prevented with novel antibiotics, the potential socioeconomic impact of the NABATIVI deliverables is enormous. With respect to chronically infected cystic fibrosis patients, new therapies would undoubtedly prove beneficial compared to standard treatments.