Many important antibiotics target the production of bacterial cell walls. The growing problem of antibiotic resistance requires innovation in the research and development process. However, scientists still have limited knowledge of how even clinically successful antibiotics kill bacteria.
A better understanding of the cellular events that precede and contribute to cell death certainly aids in developing anti-infective therapies. Peptidoglycan synthesis (PGS) is the primary mechanism for forming the bacterial cell wall.
Researchers from the University Hospital Bonn (UKB) and the University of Bonn used high-quality microscopes to study the effect of various drugs on the cell division of Staphylococcus aureus.
They discovered that the production of peptidoglycan, an important component of the bacterial cell wall, is the driving force behind the entire cell division process and that several antibiotics block cell division in just minutes. Within a few minutes they discovered how different antibiotics block cell division.
The bacterial cell wall keeps unicellular organisms in shape and integrity, and cell wall synthesis is essential for bacterial growth.
The cell division protein FtsZ produces the so-called Z ring in the center of the cell, which starts the division process. There a new cell wall is generated, with peptidoglycan as the main component. As a result of this constriction, two identical daughter cells are formed.
The model organism was chosen for study by the UKB research team led by Fabian Grein and Tanja Schneider and the team led by Ulrich Kubitscheck, professor of biophysical chemistry. The study focused on the influence of antibiotics that inhibit peptidoglycan synthesis on cell division.
Jan-Samuel Puls, a Ph.D. student at the Institute of Pharmaceutical Microbiology at UKB, said: “We found a rapid and strong effect of oxacillin and the glycopeptide antibiotics vancomycin and telavancin on cell division. The cell division protein FtsZ served as a marker here and we monitored that.”
For this reason, FtsZ was fluorescently labeled alongside other proteins. The researchers then used super-resolution microscopy to examine the effects on individual live bacterial cells over time.
They developed an automated image analysis system for microscope images, which enabled them to quickly analyze all cells in the sample under study. Dr. Fabian Grein is a scientist at the German Center for Infection Research and a junior research group leader at the UKB’s Institute for Pharmaceutical Microbiology. (DZIF), explain, “Staphylococcus aureus is about a micrometer or one-thousandth of a millimeter in diameter. That makes microscopy particularly difficult.”
The researchers from Bonn discovered that the formation of peptidoglycan is the driving force during the whole process of cell division. That inhibition of cell wall assembly by glycopeptide antibiotics in Staphylococcus aureus happens quickly and dramatically. They also discovered the specific role of essential penicillin-binding protein 2 (PBP2), which connects cell wall components in cell division. The β-lactam antibiotic oxacillin prevents this protein from being properly localized.
Grein says, “This means that PBP2 is not reaching where it is needed. This prevents the cell from dividing. Importantly, this all happens immediately after the antibiotics are added. So the first cellular effects, which have not been studied very intensively until now, are crucial.”
Given the alarming increase in antibiotic resistance worldwide, he hopes that the research results will provide a better understanding of exactly how these agents work at the cellular level and thus provide a key to the development of new antibiotics.
The results of this study will aid in the development of new antibiotics by providing a better understanding of how these drugs work at the cellular level.
- Jan-Samuel Puls, Tanja Schneider, et al. Inhibition of peptidoglycan synthesis is sufficient to completely arrest staphylococcal cell division. Scientific progress. DOI: 10.1126/sciadv.ade9023