Due to specific fatty acid sugar molecules, leprosy bacteria, among other things, can hide from our immune system. How exactly is not entirely clear. Hessel van Dijk, who received his Ph.D. on October 13, the molecules replicated and helped solve one piece of the puzzle. Van Dijk’s thesis is entitled “Synthesis of Mycobacterial Phenolic Glycolipids.”
As early as the 1950s, scientists found phenolic glycolipids (PGLs) in the cell membranes of mycobacteria such as Mycobacterium tuberculosis and M. leprae. These bacteria cause tuberculosis and leprosy. But only in recent years has serious work been done to recreate PGLs in the lab. Hessel van Dijk took on that task during his Ph.D. project, in collaboration with the University of Groningen. On October 13, the organic chemist defended his thesis.
As a rapid test for COVID-19
You can use phenolic glycolipids to diagnose leprosy, for example. The leprosy bacterium produces a certain PGL in large numbers. You can synthesize this PGL and use the molecules in an assay that works similarly to a rapid test for COVID-19. If you are infected, your antibodies will bind to the PGLs, resulting in a positive test result. “From that knowledge, the ideas started flowing. What else can we do with those molecules?”
Van Dijk calls his activities “molecular bins”. PGLs usually consist of chains of three sugar molecules and two different fatty acids. “You have to synthesize them one by one and link them via chemical reactions, a lengthy process of sometimes dozens of steps.” The sugar portion of the molecule is unique to each bacterium. “Those sugars had been replicated in previous studies, but hardly any experiments had been done with whole PGLs.”
Alarm bells and hiding: Talents of bacteria
Mycobacteria use PGLs to fool the immune system. Presumably this happens as follows. First, the bacteria make substances that alert the immune system, after which immune cells (macrophages) “eat” the invader. Once in the macrophage, the bacterium produces a substance that indicates “I’m harmless, just ignore me”, after which it can multiply in peace. Eventually, the immune cells burst, releasing hundreds of new bacteria per cell. “The bacteria can settle in your immune system for up to 20 years, until it seizes the right opportunity.”
With Van Dijk’s molecules, research partners found clues that support the hypothesis. The aforementioned PGL, which is used to diagnose leprosy, is one such compound that the immune system considers harmless. If you are one biosynthesis step away from that molecule, you have a compound that the immune system reacts very strongly to. “The current hypothesis is that the bacteria intentionally fail to complete PGL synthesis, triggering the immune system’s alarm. Once inside the macrophage, the final synthesis step occurs, resulting in a PGL that is left alone by the immune cells.”
The observation came as a surprise to Van Dijk. “A molecule that was always ignored – after all, you can’t diagnose anything with it – turned out to confirm the hypothesis. We found a new angle.” Immunologists have already worked out the results further. “My molecules can eventually lead to new drugs that, for example, prevent the bacteria from carrying out that last synthesis step. Then they can no longer fool the immune system.”
Meanwhile, Van Dijk will continue with postdoctoral research at the LUMC. It’s about sugars again, but this time without the fatty acid part. “We want to synthesize sugars found in parasitic worms in the hopes that they can be used as a diagnostic tool.”
Making tuberculosis more susceptible to antibiotics
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