PUBLICATION HIGHLIGHT
Future directions in drug development against antibiotic resistant bacteria
This publication highlight is part of the SBGrid/Meharry Medical College Communities Project, focused on science education and demonstrating how structural biology and preclinical science connect to medicine.
Antibiotic resistance is becoming an increasingly difficult problem when trying to treat bacterial infections. Some strains of gram-negative bacteria such as E. coli and Salmonella, both of which can cause serious, life threatening illnesses if not treated properly, are examples of bacteria that have developed antibiotic resistance. Gram-negative bacteria get their name from the fact that their outer membrane does not retain a violet color when dyed using the gram staining procedure. Gram staining is a technique used to classify bacteria based on the presence or absence of an outer membrane surrounding the bacteria known as a cell wall. The cell wall is what helps bacteria to be impenetrable to many medications, making treatment difficult. One of the components that contributes to the stability of the cell wall and protects the membrane from certain kinds of chemical attack is a molecule called lipopolysaccharide, or LPS.
While LPS is extremely important for the cell wall, it is not synthesized there. LPS is made in the inner membrane of bacteria and then transported to the cell wall by a group of transporter proteins called lipopolysaccharide transporter LptB₂FGC. Many antibiotics work by tearing down the cell wall in order to destroy the bacteria. Since bacteria are becoming resistant to this mechanism of action, new drugs are being developed that target the LptB₂FGC transporter to weaken the cell wall. One such drug is Zosurabalpin, which was in clinical trials at the time of publication. However, the exact mechanisms for how this class of drugs inhibit LPS transporters is unknown. In recently published work, A new antibiotic traps lipopolysaccharide in its intermembrane transporter, SBGrid member Daniel Kahne and colleagues investigated how Zosurabalpin, along with two other chemical compounds, interacted with LptB₂FGC.
By obtaining high resolution cyro-electron microscopy structures of LptB₂FGC with the three compounds tested here, they found that the drugs work by essentially trapping LSP within LptB₂FGC, therefore preventing LPS from reaching the outer membrane and weakening the cell wall. They were also able to figure out specific mutations that make E. coli and Acinetobacter resistant to these drugs. This finding was made possible by observing the specific interactions between the compounds and the transporter. The work presented by these authors will help inform future drug development efforts to treat infections caused by gram negative bacteria, especially those that are already highly resistant to current medications on the market.
Read more in Nature.
By KeAndreya Morrison, Meharry Medical College
KeAndreya Morrison is a biomedical sciences Ph.D. Candidate at Meharry Medical College studying the relationship between host and pathogen through the lens of structural biology. KeAndreya is a Georgia native where she completed her bachelor’s degree in biology at Fort Valley State University in Fort Valley, GA.
