Scientists Dig Out Genetic Cause of Typhoid Superbug
Typhoid fever remains a significant public health threat in low- and middle-income countries, with an estimated ~200,000 typhoid-associated deaths each year. Caused by Salmonella entericasubsp. enterica serovar Typhi (S. Typhi), a human-restricted monophyletic serovar of S. enterica. S. Typhi, it is transmitted from human to human by the fecal-oral route, often via contaminated water. Vaccination, access to clean water, and improved sanitation are effective means to prevent typhoid.
After antibiotics were first introduced to treat typhoid in the 1940s, typhoid’s mortality rate plummeted from around 26 percent to just 1 percent. But within 20 years the first cases of typhoid resistant to chloramphenicol—one of the three first-line treatments for typhoid appeared signaling a battle between antibiotic and bacteria.
Typhoid strains resistant to all three first-line treatments, which are known as multidrug-resistant (MDR) typhoid strains were quick to follow those resistant to only one antibiotic. And when doctors began using second-line antibiotics (more modern but expensive versions) such as fluoroquinolones, typhoid followed with resistance against those drugs, too.
Now, the Salmonella enterica serovar Typhi strain behind a current outbreak has acquired a plasmid that renders it resistant to five classes of antibiotics, according to an analysis from an international team of
researchers.A typhoid fever outbreak emerged in Pakistan in November 2016, with a number of cases, especially in Sindh Province, resistant to ceftriaxone, a third-generation cephalosporin, and to the first-line drugs chloramphenicol, ampicillin, and trimethoprim-sulfamethoxazole. The strains were also resistant to fluoroquinolones, which are used to treat multidrug resistant cases.
Now, a study by researchers at the Wellcome Sanger Institute shows the typhoid strain causing the outbreak acquired an additional piece of DNA to become resistant to multiple antibiotics, including a third-generation antibiotic.
In the spring of 2017, collaborators Professor Rumina Hasan and Dr Sadia Shakoor from the Aga Khan University in Pakistan contacted the Wellcome Sanger Institute to genetically analyse the outbreak. Sanger Institute scientists performed whole genome sequencing of typhoid samples from Pakistan to investigate the genetic cause behind its high level of antibiotic resistance.
In the course of their study, the team was able to discover the strain behind the outbreak, strain H58, a strain known to be associated with multidrug resistance. When researchers looked further, they found this strain of H58 had gained an extra strand of bacterial DNA – a plasmid – that encoded for additional antibiotic resistance genes. The typhoid possibly picked up the plasmid from E. coli.
“This is the first time we have seen an outbreak of extensively drug-resistant typhoid,” said Elizabeth Klemm, who co-led the analysis work at the Sanger Institute. “This outbreak was caused by a multidrug-resistant strain that had gone a step further and acquired an extra piece of DNA encoding additional genes for antibiotic resistance.”
Charlie Weller, head of vaccines at Britain’s Wellcome Trust global health charity, said the findings were a clear warning that “treatment options for typhoid are running out” and focussing on prevention was now vital.
Professor Gordon Dougan, a senior author from the Wellcome Sanger Institute and University of Cambridge Department of Medicine, said: “We have used genetic sequencing to uncover how this particular strain of typhoid became resistant to several key antibiotics. Sporadic cases of typhoid with these levels of antimicrobial resistance have been seen before, but this is the first time we’ve seen an ongoing outbreak – which is concerning.”
Dr Elizabeth Klemm, co-first author from the Wellcome Sanger Institute, said: “Antibiotic resistance has been mounting in typhoid for decades. This outbreak was caused by a multidrug-resistant strain that had gone a step further and acquired an extra piece of DNA encoding additional genes for antibiotic resistance. We therefore classified this strain of typhoid as extensively drug-resistant. This is the first time we have seen an outbreak of extensively drug-resistant typhoid.”
Dr Charlie Weller, Wellcome’s Head of Vaccines, said: “The treatment options for typhoid are running out. It’s time we focus on prevention, in addition to treatment. Vaccines offer another way to tackle drug resistant infections and we have a unique opportunity to address typhoid with a new Typhoid Conjugate Vaccine that has been recently prequalified by the World Health Organisation.”
