Novel Anti-Tuberculosis Compound Targets Bacterial Membrane Protein

Together, scientists from the University of Duisburg-Essen (UDE) and Heinrich Heine University Düsseldorf (HHU) have identified and synthesized a class of chemicals that can function against the tuberculosis cause in a novel way. According to a research publication in the journal Cell Chemical Biology, the so-called callyaerins work against infectious diseases through a radically different mechanism than antibiotics that have been in use up to this point.

Mycobacterium tuberculosis, or M. tuberculosis, is the bacterium that causes the infectious disease tuberculosis. Every year, the illness affects around 10 million people globally. The World Health Organization (WHO) estimates that 1.6 million people lost their lives to tuberculosis in 2021 alone.This makes it one of the most important infectious illnesses, and it poses a major threat to the populace, especially in nations with underdeveloped healthcare systems.

Treatment becomes more challenging as M. tuberculosis has become resistant to numerous drugs over time. Few medications are now on the market that can effectively combat resistant strains. As a result, in order to create entirely new medications, researchers are looking for novel antibacterial chemicals and modes of action.

One such radically novel method employing callyaerins has been discovered by a research team led by Professor Dr. Rainer Kalscheuer of the Institute of Pharmaceutical Biology and Biotechnology at HHU and Professor Dr. Markus Kaiser of the Center of Medical Biotechnology at UDE. These naturally occurring materials with a marine origin are categorized as “cyclopeptides” chemically.

The natural compound found in marine sponges has been chemically synthesized so that its effects on tuberculosis bacteria in cell cultures may be investigated. Because of this, we are now able to create novel, highly effective compounds that are not found in nature. One of the two lead authors of the study, Dr. David Podlesainski of UDE, states that successful chemical synthesis is necessary before a prospective active agent can be employed as a medicine on a broad scale. The work was just published in Cell Chemical Biology.

The human phagocytes known as macrophages are the primary host of the tuberculosis bacterium, which goes on to grow within them. It has recently been found by the researchers that callyaerins can stop the bacteria from growing in human cells.

“The callyaerins attack a specific membrane protein of M. tuberculosis called Rv2113, which is not essential for the viability of the bacterium. This comprehensively disrupts the metabolism of the bacterium, hindering its growth. By contrast, human cells remain unaffected by the callyaerins.”- Emmanuel Tola Adeniyi, Doctoral Researcher, Co-Lead Author, Heinrich-Heine University Duesseldorf

Professor Kalscheuer, corresponding author of the study: “With the callyaerins, we have discovered a new mechanism of action. Unlike other antibiotics, these substances do not block vital metabolic pathways in the bacterial cell. Instead, they directly attack a non-essential membrane protein of the bacterium, which has not been considered as a potential target before.”

Professor Kaiser, the second corresponding author, focuses on a further perspective: “In further research work, we now need to clarify precisely how callyaerins interact with Rv2113 and how this interaction disrupts various cellular processes in such a way that M. tuberculosis can no longer grow. However, we have been able to show that non-essential proteins can also represent valuable target structures for the development of novel antibiotics.”

For more information:  The anti-tubercular callyaerins target the Mycobacterium tuberculosis-specific non-essential membrane protein Rv2113, Cell Chemical Biology, doi.org/10.1016/j.chembiol.2024.06.002.