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Novel Approaches to Bacterial Target Identification, Validation and Inhibition

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Antibiotic for drug-resistant bacteria

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.

Health

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′ (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.

Keywords

Pseudomonas aeruginosa, cystic fibrosis, antibiotic resistance, genome, protegrin I, peptidomimetic, lead compounds

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