Drug Discovery Opinion

Approximately half of the world’s population is infected with Helicobacter pylori, the bacterium that causes peptic ulcers and some forms of stomach cancer. Although ‘triple therapy’ with a proton pump inhibitor and two antibiotics – selected from a very limited number – can eradicate H.pylori, an increasing number of people are found to be infected with antibiotic-resistant bacteria. Scientists in Australia, New Zealand and France have now shown that H.pylori needs vitamin B6 to establish and maintain chronic infection, and have identified two genes in the vitamin B6 biosynthesis pathway as potential targets for new antibiotics.

The team used an established technique known as in vitro attenuation to create variants of a mouse-colonising strain of H.pylori with low infectivity and then compared the gene expression profiles of the attenuated bacteria with the original highly virulent strain. The most significant changes were found to be in the genes that encode homologues of the Escherichia coli vitamin B6 biosynthesis enzymes, PdxA and PdxJ, which catalyse sequential steps in the pathway. In vitro, H. pylori PdxA mutants could only be recovered when pyridoxal-5’-phosphate, the bioactive form of vitamin B6, was added to the growth medium whereas it was not possible to produce viable bacteria with mutated PdxJ. PdxA was also shown to be necessary for H. pylori to establish a chronic infection in mice.

Further studies showed that, in addition to its well known metabolic roles, vitamin B6 is needed for the synthesis of glycosylated flagella and for flagellum-based motility in H. pylori. The study, which is published in the new open access journal mBio™, suggests that Pdx enzymes, which are present in a number of human pathogens, but not in mammalian cells, may present attractive targets for new antibiotic medicines.

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