Trench warfare: bacterial style (Image: Topham Picturepoint/Press Association Images)

Ernest Cable was a British soldier who died in 1915 from dysentery caught in the trenches of northern France during the first world war. Even if penicillin had been available to treat him, he would still have died because the bacterium that made him sick, Shigella flexneri, was already resistant to the world’s first antibiotic. That was years before Alexander Fleming discovered it in 1928.

Nor would he have been saved by erythromycin, which was discovered later, in 1949. The bacterium was found to be resistant to that too.

These historical insights into antibiotic resistance, now described as a global epidemic, come from DNA sequencing of the bacterial strain that killed Cable to mark the centenary of the first world war.


“Cable is almost like the unknown soldier in that he has no known relatives, but now everyone will remember him, so he’s been immortalised in a sense,” says Kate Baker of the Wellcome Trust Sanger Institute in Hinxton, Cambridge.

Baker says that the resistance they found is the result of an evolutionary arms race between rival microbes. Whenever one species evolves a chemical like penicillin that kills its neighbours, others will evolve resistance to it. The yeast makes an antibiotic to kill its neighbours, that might include Shigella. Sooner or later, the bacterium (and other species) will evolve resistance to the penicillin. The yeast evolves more powerful penicillin-like antibiotics, and the bugs develop resistance again, and so the cycle continues: “You have to remember penicillin is a natural compound, so bacteria living next to yeasts that make it evolve ways to evade it and survive,” says Baker.

Codenamed NCTC1, and collected in 1915 by military bacteriologist William Broughton-Alcock in the hospital in Wimereux, France, where Cable was treated, the bacterial strain was the first sample deposited in the UK National Collection of Type Cultures, which today holds 5600 strains. Cable died on 13 March 1915, aged 28, and was buried in a cemetery in Wimereux.

Now, 100 years on, the genome of the bug that killed him has been completely sequenced and compared with three more recent S. flexneri strains, one from Japan in 1954 and two from China, in 1984 and 2002.

Baker found that although 98 per cent of the bacterial DNA is still the same, the more recent strains have acquired extra genes and mutations that give them resistance to many modern antibiotics, including sulphonamides, tetracycline and other beta-lactamase antibiotics.

“They’ve kept evolving, and that’s because of the widespread clinical use of antibiotics,” she says. “Our results tell us that their evolution is very targeted, and tailored to the pressures that we’ve thrown at them.”

Baker says that mutations of the ampC gene that made the 1915 strain resistant to penicillin have since given it much broader resistance to other beta-lactamase antibiotics.

Extra genes added since 1915 have also made modern-day strains more dangerous. “The most important new virulence genes make enterotoxins, which are associated with much more severe symptoms,” says Baker. They worsen dehydration by ramping up fluid secretion by the intestine, she says.

The most recent strain, from China in 2002, had also lost a protein from its surface which would have been recognised by the immune systems of patients who’d survived infections with the earlier strains. “It means that people resistant to the older strains would have been susceptible to the disease again, because their immune systems wouldn’t recognise the strain without the surface protein,” says Baker.

The insights from the historical comparison could be valuable for designing a vaccine against shigella, which still kills 750,000 children under 5 each year.

“By showing us what parts of the genome have been constant for the past 100 years, historical isolates can help us select vaccine targets, to make sure we don’t target any parts that have changed over time,” says Baker. The institute has also produced a short film describing the project, and an account of how private cable was identified and traced.

Other bacteriologists said that the 1915 strain harboured the resistance expected for the pre-antibiotic era, to penicillin-like compounds through the ampC gene and to erythromycin through mechanisms for physically pumping the antibiotic out of the bacterial cell. The more recent strains, by contrast, add resistance to a host of antibiotics introduced over the past 60 years. “These bookend sequences show the impact of antibiotic use and resistance evolution in the antibiotic era,” says Gerry Wright of McMaster University in Hamilton, Ontario, Canada.

Journal reference: The Lancet, DOI: 10.1016/S0140-6736(14)61789-X

Historical account of how the sample was collected: The Lancet, DOI: 10.1016/S0140-6736(14)61790-6