BOSTON – At the annual meeting of the American Society for Microbiology last week, the spotlight was on bugs that might turn into the next pandemic. But it was also clear that some of the next emerging threats are already here.

In a session on "Spread of Antimicrobial Resistant Organisms: Global Threats," scientists talked about the deep inroads that drug-resistant bacteria have made. Some of those bugs, both old and new, are set to erase the gains made in the antibiotic era.

But both drug development and new uses of genomic data could help to stave off the post-antibiotic era, as examples at the conference, and in the scientific journals, showed last week.

Given the challenges of tuberculosis (TB), the pipeline for new TB drugs is in good shape. In 2012, the FDA approved Sirturo (bedaquiline, Janssen Pharmaceuticals) for MDR-TB. The working group on new TB drugs lists another four drugs currently in phase III, as well as nine trials of seven agents in phase II.

But the difficulties both in developing and effectively deploying such drugs are formidable. "It's easy to say, 'We just need more money,'" Barry Kreiswirth said in a talk at the ASM conference. "But there's really some unusual challenges with TB."

For one, tuberculosis is in an unholy alliance with the AIDS virus, which has fueled both its spread and its lethality. In one 2006 outbreak of extensively drug-resistant tuberculosis (XDR-TB, which is one step further along the resistance road than multidrugresistant, or MDR-TB), the median survival time was 16 days, with the overall survival curve looking like something that might be presented at the American Society of Clinical Oncology meeting.

In that outbreak, which was reported at the 2006 XVI International AIDS conference, every one of the individuals with XDR-TB was also infected with HIV. For drug developers, this means that not only do new drugs have to work against TB strains that are more difficult to treat than they once were – they have to do so while being neutral or synergistic with the HIV drugs those patients need.

TIME WASTING

Mycobacterium tuberculosis also grows slowly – so slowly, in fact, that it takes three months to determine whether a case is multidrug resistant or not. That glacial pace wastes valuable time, adds to the overall duration of treatment – which, for drug-resistant TB strains, is already nearly two years – and brings endless opportunities for the development of yet more resistant strains.

Of note, the slow growth of TB is one area where more money could make a difference. No, the bug cannot be paid to grow more quickly. But if patient isolates were sequenced rather than cultured, genomic resistance signatures could be identified in a week.

Such sequencing is not used even in the developed world, where it would be realistic to do so. In a comment published in the May 22, 2014, issue of Nature, Cambridge University's Sharon Peacock argued that it should be.

Pathogen sequencing was once seen as a way to identify new vulnerabilities and develop narrow-spectrum antibiotics. For those particular uses, its results have disappointed, at least so far. There is not one antibacterial drug on the market that has resulted from pathogen sequencing.

But for determining drug resistance, Peacock wrote, "pathogen sequencing represents a quick win. Bench-top sequencers that cost around $125,000 can complete several bacterial genomes in a day, at a cost of around $150 per sample – about twice as much as running some commercial [polymerase chain reaction] tests that detect resistance to one drug at a time."

In her commentary, Peacock said such sequencing could be used to predict resistance of a given strain, as well as trace outbreaks, and could serve as an early warning system for the emergence of new resistant strains.

ROUTE SEQUENCING

Sequencing is already routinely done for HIV patients to detect the emergence of resistant strains, though Peacock noted that the types of analyses that would be used to detect resistance in an acute bacterial infection differ from those that are best for chronic viral infections, and different again from those that are best for tracking outbreaks.

In the work of Peacock and her colleagues, sequencing was informative not just for M. tuberculosis, but for bacteria that currently are still a much bigger problem in Europe and North America: drug-resistant infections that are picked up in hospitals, also known as nosocomial or health care-associated infections.

The Infectious Disease Society of America has identified a group of six pathogens, the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter species), as those that cause the majority of hospital-acquired infections and are in effect escaping the modern antibiotic era.

Peacock wrote in her commentary that "sequencing is informative in all species tested so far, including Acinetobacter baumannii and Klebsiella pneumonia."

Another way in which genomics could be brought to bear on antibiotic resistance is by looking for clues, not in the pathogens but in the immune systems of infected individuals who have varying degrees of resistance to them. The possibilities of that approach were elaborated in another commentary last week, this one by the University of Edinburgh's Kenneth Baillie in the May 23, 2014, issue of Science.

Baillie noted that "susceptibility to infectious disease is one of the most strongly inherited of all common disease traits," and that host genetic variants that protect against infections tell us exactly what we want to know – namely, what it takes for the immune system to come out the winner in the war on bugs.

One example, though not one that is likely to become widespread, is "Berlin patient" Timothy Ray Brown, whose bone marrow transplant for leukemia also cured him of AIDS, by rendering his T cells immune to the virus.

There are also examples that point to less extreme interventions. A variant in a magnesium transporter, for example, is linked to a susceptibility to Epstein-Barr virus infection, and magnesium helps control the infection.

As with sequencing of the pathogens themselves, sequencing of patients is challenging within the context of an acute infection. But Baillie argued that such sequencing can be useful to understand general rules of susceptibility, as well as possibly to help some individual patients.

"When a patient dies of an infection, we rarely pause to think that a weakness for that specific pathogen may have been present in that individual, right from the start, encoded in their genome," he wrote. "By interrogating these weaknesses, we are finding clues that may, in time, help us to save more people from the same fate."