A recent study has shown that disabling bacterial flagella could prove to be an effective new method by which to fight some bacterial infections.
A recent study has shown that disabling bacterial flagella could prove to be an effective new method by which to fight some bacterial infections. Dr. Hideyuki Matsunami, Okinawa Institute of Science and Technology (OIST) Graduate University, Kunigami District, Japan, and colleagues published the results of their study in Scientific Reports.
Researchers continue to investigate alternatives to antibiotics for various reasons. One particular problem is that these drugs indiscriminately kill all bacteria—including beneficial or commensal organisms in the body. The ability to disrupt bacterial infections by targeting just the pathogenic organism would therefore be a great advantage for clinicians who are trying to control bacterial infections. In a press release on the OIST Graduate University website, Professor Fadel Samatey, one of the study’s authors, emphasizes how “[o]ne way to do that would be to disrupt the bacteria’s motility, which means to disrupt the flagella”. According to the authors, there is a clear correlation between bacterial motility and infection.
Flagella are long, whip-like appendages that protrude from the surface of motile bacteria and rotate, allowing the bacteria to move. These appendages consist of three major parts: a filament, which acts as a propeller for bacterial motility and contains the protein flagellin (Flg); a basal body, which contains proteins involved in filament rotation; and a hook, which transmits motor torque to the filament.
The researchers therefore conducted a study to investigate some important aspects of the formation of flagella in Salmonella enterica serovar Typhimurium. In particular, they examined the three-dimensional crystal structure of FlgA—a flagellar chaperone protein with a critical role in early flagellar development.
They found that FlgA exists in two conformations—open and closed forms. Although these two forms are chemically similar, the geometrical arrangement of their structural units is different. This difference has important implications for flagellar development, the authors say.
During flagellar development, flagellar proteins are typically produced inside the bacterium and are later released through a channel to the outer surface of the bacterium. These include flagellar proteins such as FlgI which is a key component of the P-ring—a ring-shaped protein in the basal body. According to the authors, “P-ring formation is a key step enabling the bacterial flagellum to pass through the outer membrane”. FlgA interacts with FlgI during P-ring formation, and functions as a chaperone in the process.
The researchers showed that structural flexibility is essential for FlgA function and P-ring formation. They found that the closed form of FlgA is structurally narrower and more compact than the open form, and a key region of the closed form is less flexible. Overall, this closed conformation makes it impossible for developing flagella to extend outside the bacterium, because the channels that usually allow the flagella to extrude through the bacterial membrane do not form. “[T]he closed form of FlgA can bind to FlgI, but cannot proceed with the subsequent steps, thereby preventing FlgI from forming the P-ring,” the authors write.
Although the mechanism by which FlgA switches conformations from the closed to the open form remains unknown, the authors hypothesize that the switch may occur after FlgA interacts with cellular components or other flagellar proteins. “[C]rystal structures of FlgA will allow future mutagenesis studies to better define its role in FlgI stabilization, polymerization, and localization, as a molecular chaperone in flagellar P-ring formation,” Dr Matsunami and colleagues write.
And, because flagellation of cells cannot occur in most Gram-negative bacteria in the absence of FlgA, the authors note that FlgA might therefore be a target for novel antimicrobial drugs to inhibit cell flagellation and motility. “Further structural information about the FlgA-FlgI complex would be advantageous in the pursuit of new therapeutic drugs,” they conclude.
Dr. Parry graduated from the University of Liverpool, England in 1997 and is a board-certified veterinary pathologist. After 13 years working in academia, she founded Midwest Veterinary Pathology, LLC where she now works as a private consultant. She is passionate about veterinary education and serves on the Indiana Veterinary Medical Association’s Continuing Education Committee. She regularly writes continuing education articles for veterinary organizations and journals, and has also served on the American College of Veterinary Pathologists’ Examination Committee and Education Committee.