Existing antibiotics can wipe out active bacteria, but they generally work poorly against persister, bacteria that are dormant, which are often the reason treatments of chronic bacterial infections fail. For instance, tuberculosis notoriously resists many antibiotics when dormant, helping lead to roughly 1.4 million deaths annually worldwide. Now scientists have developed a strategy to identify drugs that can fight persisters, and show it could help wipe out both standard and persister tuberculosis bacteria in mice, report findings detailed in the Proceedings of the National Academy of Sciences.
Scientists developed a strategy to identify proteins tuberculosis bacteria need to both grow when active and persist when dormant. This involves testing a target of interest — a gene and the protein it encodes for — by simultaneously repressing transcription of the target gene and degrading the protein that gene encodes for. (Often strategies that analyze targets for potential drugs do one but not the other.) This system, which the researchers call a dual-control switch, involves genetically modifying an organism so that giving it a single molecule, either the organic compounds anhydrotetracycline or doxycycline, accomplishes both tasks.
The researchers approached proteins required by both replicating and nonreplicating tuberculosis bacteria as potential targets. They focused on nicotinamide adenine dinucleotide (NAD), an essential molecule for numerous biochemical reactions.
Molecular biologist Dirk Schnappinger at Weill Cornell Medical College in New York and his colleagues found depleting NAD synthetase (NadE) rapidly killed the bacteria in mice during both acute and chronic tuberculosis infections.
“Mycobacterium tuberculosis (Mtb) is a biosafety level 3 pathogen — you can get infected by breathing and the bug can kill you — and Mtb grows very slowly. That’s pretty close to a microbial geneticist’s worst nightmare — mistakes and failures cost a lot of time,” Schnappinger says. The first authors on the paper are Jee-Hyun Kim, who moved on to a postdoc position at the University of Southern California, and Kathryn O’Brien, still a graduate student in Schnappinger’s lab.
Identifying compounds that strongly inhibit NadE in tuberculosis bacteria “and have little or no toxicity in humans remains a major challenge,” Schnappinger warns. “NadE might prove not to be druggable.”
Still, the researchers hope drugs can be developed against tuberculosis using this strategy, and are collaborating with academia and industry to try and do so. In addition, persisters are found not only in tuberculosis, but also with salmonellosis and cystic fibrosis-associated lung infections, which could be future targets.