Alternatives to antibiotics-a pipeline portfolio review.

Antibiotics have saved countless lives and enabled the development of modern medicine over the past 70 years. However, it is clear that the success of antibiotics might only have been temporary and we now expect a long-term and perhaps never-ending challenge to find new therapies to combat antibiotic-resistant bacteria. A broader approach to address bacterial infection is needed. In this Review, we discuss alternatives to antibiotics, which we defined as non-compound approaches (products other than classic antibacterial agents) that target bacteria or any approaches that target the host. The most advanced approaches are antibodies, probiotics, and vaccines in phase 2 and phase 3 trials. This first wave of alternatives to antibiotics will probably best serve as adjunctive or preventive therapies, which suggests that conventional antibiotics are still needed. Funding of more than £1·5 billion is needed over 10 years to test and develop these alternatives to antibiotics. Investment needs to be partnered with translational expertise and targeted to support the validation of these approaches in phase 2 trials, which would be a catalyst for active engagement and investment by the pharmaceutical and biotechnology industry. Only a sustained, concerted, and coordinated international effort will provide the solutions needed for the future.

Physical map of the chromosome of Aeromonas salmonicida and genomic comparisons between Aeromonas strains.

I-Ceul and Pmel physical maps of the Aeromonas salmonicida A449 chromosome were constructed using PFGE. The circular chromosome of A. salmonicida A449 was estimated to be 4658 +/- 30 kb. The approximate location of several genes, including those encoding proteins implicated in virulence, were identified. The map showed that the known virulence-factor-encoding genes were not clustered. The I-Ceul genomic digestion fingerprints of several typical and atypical strains of A. salmonicida were compared. The results confirmed the homogeneity of typical strains, which provided further support for the clonality of the population structure of this group. Extensive diversity was observed in the I-Ceul digestion fingerprint of atypical strains, although a clonality was observed in the strains isolated from diseased goldfish. The results suggest that comparison of I-Ceul digestion fingerprints could be used as a powerful taxonomic tool to subdivide the atypical strains and also help clarify some of the current confusion associated with the taxonomy of the genus Aeromonas.

DNA sequence and mutational analyses of the pVir plasmid of Campylobacter jejuni 81-176.

The circular pVir plasmid of Campylobacter jejuni strain 81-176 was determined to be 37,468 nucleotides in length with a G+C content of 26%. A total of 83% of the plasmid represented coding information, and all but 2 of the 54 predicted open reading frames were encoded on the same DNA strand. There were seven genes on the plasmid in a continguous region of 8.9 kb that encoded orthologs of type IV secretion proteins found in Helicobacter pylori, including four that have been described previously (D. J. Bacon, R. A. Alm, D. H. Burr, L. Hu, D. J. Kopecko, C. P. Ewing, T. J. Trust, and P. Guerry, Infect. Immun. 68:4384-4390, 2000). There were seven other pVir-encoded proteins that showed significant similarities to proteins encoded by the plasticity zones of either H. pylori J99 or 26695. Mutational analyses of 19 plasmid genes identified 5 additional genes that affect in vitro invasion of intestinal epithelial cells. These included one additional gene encoding a component of a type IV secretion system, an ortholog of Cj0041 from the chromosome of C. jejuni NCTC 11168, two Campylobacter plasmid-specific genes, and an ortholog of HP0996 from the plasticity zone of H. pylori 26695.