The introduction of antibiotics during the middle of the 20th century changed the course of human health, curing once fatal infections. But the misuse and overuse of antibiotics has led to the evolution of many bacterial strains that are resistant to currently available medicines.
One group of bacteria, known as Gram-negative, presents an especially difficult challenge because these single-celled organisms are encased in two membranes as opposed to one. That extra layer makes it more difficult for antibiotic medicines to penetrate the cell. Gram-negative bacteria include Escherichia coli (E. coli), some strains of which can cause foodborne illness, and Neisseria gonorrhoeae, which causes gonorrhea. Other species of Gram-negative bacteria cause many hospital-associated infections.
Our scientists are working to tackle antibiotic resistance through various approaches. In 2018, a team led by Peter Smith, Michael Koehler and Christopher Heise helped develop the first new class of antibiotics for Gram-negative bacteria in nearly 50 years. More recently, Kelly Storek, Steven Rutherford and their team have been exploring the possibility that proteins embedded in the outer membrane of Gram-negative bacteria could be targets for new antibiotics.
Kelly and Steven’s team previously showed that a monoclonal antibody designed to bind a specific protein in the outer membrane of E. coli was able to disrupt the integrity of the outer membrane and kill the bacteria. Now the team has published a study in eLife that shows a new way to systematically probe the exposed parts of outer membrane proteins for points of vulnerability. The paper demonstrates the technique by looking at an outer membrane protein called LptD.
LptD is an essential protein that is common across many different types of Gram-negative bacteria. It helps to build the components of the outer membrane and is critical for the growth and survival of bacteria, making it a promising target to potentially inhibit with new antibacterial molecules.
A multidisciplinary team spanning infectious diseases, antibody engineering, structural biology, and biochemical and cellular pharmacology built and analyzed a custom library of more than 3,000 antibodies, each designed to bind a different part of the exposed regions of LptD on the bacterial surface. Their approach represents one of the most comprehensive antibody-enabled investigations of any membrane protein described to date. Interestingly, even though this collection of antibodies targeted almost all of the extracellular structure, none of them disrupted LptD’s function. This suggests that the antibody-accessible portions of LptD are not essential and may even have evolved to protect critical regions of LptD from the extracellular environment to provide a survival advantage.
Although the study did not identify any external targets that affected LptD’s function, it did point researchers toward other potentially vulnerable parts of LptD and showed how other outer membrane proteins could be similarly probed in future studies to combat antibiotic resistance.
To learn more about this research, you can visit the eLife journal website.