Key to success of drug-resistant bacteria

Date:
April 8, 2022
Source:
Columbia University Irving Medical Center
Summary:
Researchers have uncovered how Gram-negative bacteria -- which cause
a variety of drug-resistant infections -- build their protective
outer layer, which could lead to more effective treatments.



FULL STORY ========================================================================== Researchers have discovered how Gram-negative bacteria -- which cause
drug- resistant pneumonia, bloodstream infections, and surgical site
infections in hospitalized patients -- finish building a crucial component
of their outer membrane that shields these pathogens from attacks by
the immune system and antibiotics. The new findings could accelerate
the development of novel drugs to counteract these potentially deadly
bacteria, the source of countless infections in health care settings
worldwide.


==========================================================================
The study was published online April 6 in Nature.

"Previously, we knew that Gram-negative bacteria construct their outer
membrane with two main, non-protein components -- lipids and sugars --
which together form an impermeable barrier. The missing link was how this lipopolysaccharide component comes together," says Filippo Mancia, PhD,
a co-leader of the study and professor of physiology & cellular biophysics
at Columbia University Vagelos College of Physicians and Surgeons.

Using cutting-edge single-particle cryo-electron microscopy, Mancia and colleagues were able to determine the structures of the enzyme that
links together the lipids and sugars (called an O-antigen ligase),
in two different functional configurations. Then, combining genetic, biochemical, and molecular dynamics experiments, the team learned how
the enzyme positions the lipids and sugars so that they can combine to
form the protective membrane.

The lipopolysaccharide component of the outer membrane is critical to
the survival of Gram-negative bacteria. "If you could block its assembly,
then you would make the bacteria more sensitive to antibiotics and more vulnerable to the immune system," Mancia says.

Construction of this membrane is an ongoing process, beginning when
Gram- negative bacteria are first formed and continuing as the membrane naturally degrades and requires repair. "This means that we would have
many opportunities to disrupt the membrane, not just at one stage of
the bacteria's life cycle," Mancia says.

After revealing the structure of the enzyme that performs the last and
critical step in assembling lipopolysaccharide barriers in drug-resistant bacteria, the researchers may begin to custom-design drugs that inhibit
the biosynthesis of this protective membrane.


========================================================================== Story Source: Materials provided by
Columbia_University_Irving_Medical_Center. Note: Content may be edited
for style and length.


========================================================================== Journal Reference:
1. Khuram U. Ashraf, Rie Nygaard, Owen N. Vickery, Satchal
K. Erramilli,
Carmen M. Herrera, Thomas H. McConville, Vasileios I. Petrou,
Sabrina I.

Giacometti, Meagan Belcher Dufrisne, Kamil Nosol, Allen
P. Zinkle, Chris L. B. Graham, Michael Loukeris, Brian Kloss,
Karolina Skorupinska-Tudek, Ewa Swiezewska, David I. Roper, Oliver
B. Clarke, Anne-Catrin Uhlemann, Anthony A. Kossiakoff, M. Stephen
Trent, Phillip J. Stansfeld, Filippo Mancia. Structural basis of
lipopolysaccharide maturation by the O- antigen ligase. Nature,
2022; DOI: 10.1038/s41586-022-04555-x ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/04/220408131754.htm

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