‘This microbe is faster than us’

Last year, tuberculosis infected and killed more people worldwide than any other infectious disease, disproportionately affecting people in impoverished nations. Part of TB’s treachery: its ability to rapidly adapt to resist antibiotics.

The World Health Organization has endorsed quick and effective methods for detecting antibiotic-resistant strains of tuberculosis, but recent evidence suggests that the bacteria that cause TB are outpacing our technology. Some strains with antibiotic resistance go undetected by top-of-the-line diagnostic tests. Undetected and mistreated, resistant tuberculosis spreads.

The next step in TB eradication: tracking down this antibiotic-resistant enemy that’s flying beneath the radar.

The WHO’s testing methods catch 95 percent of the resistant bugs, says Emmanuel Andre, a microbiologist at the Catholic University of Leuven in Belgium. But that evasive 5 percent could be dangerous.

Concerned that resistant tuberculosis might lurk undetected amid South African populations, Andre and his colleagues analyzed TB samples taken between 2013 and 2017 from people in four different provinces of the country.

Some of the South African tuberculosis samples carried a specific combination of mutations that make them resistant to the two most potent tuberculosis drugs available: isoniazid and rifampicin.

Screening the bacteria using WHO methods, however, only revealed resistance to isoniazid. The bacteria had developed a new mutation for resistance to rifampicin that eluded the standard tests.

Unfortunately, people infected with this sneaky form of TB endured rounds of ineffective medications because their resistance to rifampicin was unknown.

“Not only do they have an adverse outcome, but they remain infectious longer, spreading the disease further,” Andre says. His team published their findings in the health journal The Lancet.

Andre is not the only scientist focusing on drug-resistant TB strains. Five years ago, Oxford microbiologist Tim Walker and his colleagues began looking for faster, more accurate ways to diagnose all tuberculosis — including resistant strains — using genome sequencing.

By collaborating with researchers from 16 countries across six continents, Walker and his group analyzed the genomes of more than 10,000 strains of tuberculosis, according to a study published weeks before the South African study in the New England Journal of Medicine.

After sequencing the bacteria’s genome, Walker’s team identified patterns in the DNA known to cause resistance. This sequencing method was just as effective as WHO methods at predicting which TB samples were resistant to the most widely used antibiotics.

For South Africa, and arguably many other regions of the world, this genome-sequencing technology cannot come soon enough. Current WHO diagnostics use a time-consuming, lab-based technology known as PCR (polymerase chain reaction) instead of gene sequencing. PCR only looks at certain sites in the genome, and it can’t find mutations that it’s not designed to look for.

Sequencing genomes to diagnose TB would give doctors a more complete picture, revealing resistance-causing mutations that current methods might miss, as well as any novel mutations. And sequencing has the potential to be used in even the most remote areas.

The analysis of the first 10,000 TB samples with genome sequencing is proof of principle, Walker says. In these samples, his team could predict how susceptible a strain would be to first-line TB drugs by identifying specific patterns in the DNA sequence.

Walker’s team used colorful, florescent tags to label the four different building blocks of DNA, called nucleotides, to reveal the patterns that make up genes. The team could search for genes known to cause antibiotic resistance, all in a fraction of the time the WHO methods take. Yet predicting resistance with DNA sequencing is still a few years away.

“Part of the problem is that we don’t actually have a comprehensive list of genes associated with resistance,” says Dr. Tawanda Gumbo, a researcher and member of the WHO Task Force on Tuberculosis Medicines.

But a transition to diagnosing via genome sequencing might be necessary to achieve full eradication of tuberculosis. “Getting people on the right drugs currently, while dependent on laboratories, is not going to happen. It’s too expensive, too difficult,” Walker says.

And people need the right drugs. Mistreating resistant tuberculosis only increases the bacteria’s resistance and escalates contagion.

Andre agrees that genomic sequencing has to be the new form of diagnosis, but until then, he says other countries should survey TB patients for undetected resistance, as his South African study did.

The United Nations has called in recent years for an end to TB by 2030. To meet the UN’s 2030 deadline “we clearly need to be a little more dynamic and proactive,” Andre says, “because this microbe is faster than us.”