The mystery of why mycobacteria-a family which includes the microbe that triggers TB-are extraordinarily hardy organisms has been unraveled by University of Otago, New Zealand, research that provides new hope for developing a revolutionary class of antibiotics to tackle TB.
Together with researchers in the US and Germany, Otago microbiologists have teased the mechanisms through which the aerobic soil microbe Mycobacterium smegmatis is able to persist for extreme lengths of your time within the absence, or near-absence, of oxygen.
Their findings, published now in the prestigious US journal PNAS, reveal that hydrogen is really a key factor that enables mycobacteria to survive oxygen-limitation over long stretches.
The team, led by Professor Greg Cook, found that in such conditions the bacterium has the capacity to quickly switch its cellular metabolism from a primarily oxygen-based one over to one which uses fermentation for energy production instead.
This metabolic mode depends on the production and recycling of molecular hydrogen, a high-energy fuel and diffusible gas. These cells produce hydrogen to make sure their survival until they once more have access to sufficient oxygen for growth.
Professor Cook says it had always been a puzzle how mycobacteria generate energy when in their oxygen-starved dormant states.
“Mycobacteria grow through combusting their preferred carbon-based fuel sources using oxygen. However, they can also somehow survive for months or years when their supply of oxygen is exhausted.
“For example, in individuals with latent TB infections, Mycobacterium tuberculosis bacteria are walled in by clumps of immune and other cells with what is believed to be an incredibly low oxygen environment. However, such patients should be monitored for the rest of their resides in case the bacteria become active again,” he states.
Professor Cook’s team have established that Mycobacterium smegmatis metabolizes molecular hydrogen using three enzymes called hydrogenases. One hydrogenase produces hydrogen, whereas the other two consume it. These hydrogenases are activated under oxygen starvation with a master regulator called DosR.
The researchers found that strains of Mycobacterium smegmatis in which the genes for the hydrogenases or the regulator DosR have been ‘knocked out’ experienced a hundredfold reduction in the long-term survival compared to the normal bacterium, he says.
His team is currently testing whether these bits of information are extendable to Mycobacterium tuberculosis, which activates a further predicted hydrogenase under low oxygen conditions.
“If knocking out this other hydrogenase also drastically reduces long-term survival, the enzyme might end up becoming an excellent next-generation drug target in latent TB infections, which around one-third of the world’s population suffer.”
The Otago researchers’ studies on hydrogen fermentation in mycobacteria have been performed in collaboration with Professor William Jacobs Jr., a world-leading bacterial geneticist at the Albert Einstein College of Medicine in Ny, who is known as the ‘TB terminator’.
One of the paper’s lead authors is Dr Michael Berney, an old research fellow in Professor Cook’s laboratory who is now an Assistant Professor associated with Professor Jacobs’ laboratory. The other co-authors include Professor Cook, Dr Chris Greening, who also co-led the study and recently completed his PhD studies in the Cook Laboratory, and Professor Dr Ralf Conrad, director of the Max-Planck Institute for Terrestrial Microbiology in Marburg, Germany.
The study was funded through the Royal Society of recent Zealand’s Marsden Fund.
