Though the infectious bacteria that cause dangerous diseases like gastric cancer, Q fever, Legionnaires' disease, whooping cough are each different, they all use similar molecular machinery to infect human cells. Bacteria use this machinery called a Type IV secretion system (T4SS), to inject toxic molecules into cells and also to spread genes for antibiotic resistance to fellow bacteria,
Caltech's researchers have now shown the 3D molecular architecture of the T4SS from the human pathogen Legionella pneumophila with unprecedented details. In the future, this discovery could enable the development of precisely targeted antibiotics for the diseases mentioned above.
The team performed this research in the laboratory of Grant Jensen, professor of biophysics and biology and Howard Hughes Medical Institute investigator, in collaboration with the laboratory of Joseph Vogel at the Washington University School of Medicine in St. Louis (WUSTL). The team published the research in the journal Nature Microbiology.
There are nine different kinds of bacterial secretion systems. The most elaborate and versatile among them is Type IV. A T4SS can ferry a wide variety of toxic molecules, up to 300 at once, from a bacterium into its cellular victim, hijacking cellular functions and overwhelming the cell's diseases.
The year 2017 saw Caltech postdoctoral scholar Debnath Ghosal, one of the first co-author of the study, and his colleagues using a technique called electron cryotomography to reveal, for the first time, the overall low-resolution architecture of the T4SS in Legionella, the bacteria that causes Legionnaires' disease, a severe and often lethal form of pneumonia.
With Kwang-Cheol Jeong of WUSTL and their collaborators, Ghosal now made a detailed structural model of this dynamic multi-component machine. The team also made precise perturbations to the bacterium's gene to study mutant versions of the T4SS, showing how this complex machine organizes and assembles.
The model revealed that the secretion system is composed of a distinct chamber and a long channel, like the chamber and barrel of a gun. Characterizing these and other components of the T4SS could enable the development of precisely targeted antibiotics.
Current antibiotics act broadly and wipe out bacteria throughout the body, including the beneficial microorganisms that live in the human gut. In the future, antibiotics could be designed to block only the toxin delivery systems (such as the T4SS) of harmful pathogens, rendering the bacteria inert and harmless without perturbing the body's so-called "good bacteria."
