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The research project "Identification and validation of novel drug targets in Gram-negative bacteria by global search: a trans-system approach" –AntiPathoGN- was launched in February 2009 by a consortium of ten institutions –academic and industrial- from three European countries. With a duration of four and a half years, this Collaborative Project has been supported by funding under the Seventh Framework Programme of the European Union.
The increasing emergence and spread of multidrug-resistant (MDR) pathogens currently constitutes one of the major threats to public health worldwide. The shortage of effective antimicrobials for the treatment of infections caused by MDR Gram-negative bacteria is particularly critical, as strains within this group have already become the main cause of death among patients with hospital-acquired infections. In this context, AntiPathoGN seeks to discover new targets and modes of action, less propitious to the evolution of resistance, for the development of drugs against Gram-negative bacteria. To this end, the consortium has developed a strategy based on a comparative, system-level analysis of proteins and protein-interaction networks of the bacteria of interest with enrichment of factors involved in pathogenesis, virulence, drug resistance and cell division/growth. Main target bacteria of AntiPathoGN include high-priority MDR pathogens such as Pseudomonas aeruginosa, Escherichia coli and Acinetobacter baumannii, and emerging ones such as Helicobacter pylori and Stenotrophomonas maltophilia. In addition to the identification and validation of new drug targets, the AntiPathoGN project pursues the discovery of novel antibacterial compounds acting against these targets by screening purpose-specific libraries of products derived from natural sources and from synthetic compounds.
At formal closing, the consortium has identified and validated phenotypically eighteen potential antimicrobial targets in Gram-negative bacteria, and has found hit compounds against two of them. Two of the targets are essential for bacterial growth, while the other sixteen are involved in various mechanisms related to virulence or resistance. Cell-based screens have also identified 33 natural products with antimicrobial activity, including three novel compounds. Further studies will be needed to confirm the potential of these targets and compounds for antimicrobial drug development. The experimental interactome data and bioinformatic databases and tools generated by the consortium constitute a fundamental contribution of AntiPathoGN to the research community, within and beyond the field of antimicrobial-drug discovery.