Since pathogenic microbes rapidly develop resistance against existing antibiotics, new anti-infective strategies are needed to keep ahead of the inevitable resistance that accompanies antimicrobial use. Since metabolism is a prerequisite for virulence, such pathways could potentially be good targets for anti-microbial therapies. Bacterial in vivo metabolism is one of the most fundamental aspects of virulence of pathogenic bacteria yet our understanding of it is relatively limited.
Our current view of bacterial metabolism in host tissues is largely derived from investigation of deletion mutants within inbred mouse models and transcriptional data obtained during infection models. Some of the current data derived from in vivo
high-throughput screens aiming at identifying genes essential for infection are inconsistent with each other: the essential genes depend on the model system used, the type of infection and the route of inoculation. It also underlines that high-throughput screens should be considered with some caution since their results might not necessarily be generalized to other infection models, especially when it comes to metabolic genes [69
While comparative genomics should identify new pathways unique to specific pathogens or associated with virulence genes, new strategies for the analysis of the importance of specific metabolic pathways in host tissues must be developed. Particularly promising is the use of isotopes to elucidate real carbon and nitrogen sources for pathogens over the course of an infection [70
The role of metabolism in virulence should then be increasingly recognized as a priority equivalent to studying classical virulence factors (). Metabolic genes are often identified by these studies but are rarely further investigated. Missing metabolic pathways in genomes from pathogens has also been dismissed as the result of lack of selection due to the nutrient-rich environment in the host. However, new data suggest that this loss might be advantageous for virulence [50
]. Future studies could focus on those bacterial metabolic genes possibly involved in host-pathogen interactions.
Until now, antimicrobial therapies based on interference with bacterial metabolism have been limited. Recently bacterial virulence factors have begun to be re-considered as possible therapeutic targets. The idea that inhibition of bacterial virulence characteristics could be used therapeutically is attractive since it would not require that antimicrobials kill bacteria and hence select for resistance within the microbial target as well as commensal bystanders. Bacterial urease is a target for the development of such drugs which could lead to new therapeutics to manage gastric and urinary tract infections. Hydroxamic acids or phosphoro-diamidates strongly inhibit ureases in vitro
and one compound (acetohydroxamic acid) is already available in some countries as adjunctive therapy in patients with chronic urea-splitting urinary infection [39
]. In the same vein, interruption of iron trafficking is a plausible but still largely unproven means of clinically controlling pathogens [72
In conclusion, a greater understanding of bacterial metabolism specific to infection of multicellular organisms should ultimately lead to a deeper understanding of bacterial pathogenesis as well as host metabolism. It might also identify new strategies for antimicrobial chemotherapy that would be specific to pathogens.