Antibiotics have long been an indispensable tool in combating bacterial infections, but their widespread use has also led to a growing concern: antibiotic resistance. This poses a significant threat to global public health, as it renders existing medications less effective, making infections harder to treat. A solution to this problem may lie in the development of next-generation antibiotics that specifically target bacterial processes while sparing human cells.
A promising advancement in this area has emerged from a team of international researchers, led by the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), in collaboration with Saarland University. Their recent research focuses on the development of novel drug candidates targeting a metabolic pathway present only in bacterial cells, ensuring the drugs remain toxic to pathogens while being harmless to human cells. This breakthrough could offer new hope in the fight against antibiotic-resistant infections.
The Challenge: Bacteria vs. Human Cells
The delicate balance of creating antibiotics that are toxic to harmful bacteria but safe for the human body is what makes antibiotic development such a complex science. Bacterial cells differ significantly from human and animal cells in their structure and function. One of the most notable differences is the presence of a rigid cell wall in bacteria, which human cells lack. Targeting the biosynthesis of these cell walls was one of the earliest approaches to developing antibiotics, and it remains an effective way of ensuring that antibiotics act specifically on bacteria and not on human cells.
However, over time, bacteria have developed resistance to some of these conventional antibiotics, making the search for new targets in bacterial metabolism increasingly urgent. In response to this challenge, the research team at HIPS has turned to a lesser-known yet critical aspect of bacterial metabolism: the methylerythritol phosphate (MEP) pathway. By targeting this unique pathway, the researchers have developed new antibiotic candidates that hold promise against antibiotic-resistant pathogens.
Exploring the MEP Pathway: A Unique Metabolic Target
The MEP pathway plays an essential role in the energy metabolism of several bacteria, including Pseudomonas aeruginosa, a notorious pathogen often responsible for hospital-acquired infections. This pathway is responsible for the production of vital molecules that bacteria need for growth and survival, such as isoprenoid compounds. Importantly, human cells do not possess the MEP pathway, meaning any drug that targets this system would have no effect on human cells, offering a significant advantage in terms of selectivity and safety.
Blocking the MEP pathway in bacteria, such as through the inhibition of a key enzyme, would cripple their metabolism, effectively halting their growth and leading to their death. This mechanism is the focus of the new antibiotic candidates developed by Prof. Anna Hirsch and her team at HIPS. By targeting enzymes in the MEP pathway, the team has found a way to create antibiotics that are highly specific to bacteria, while avoiding toxicity to human cells.
In-Depth Analysis of the IspD Enzyme
A critical step in advancing this new antibiotic approach was understanding the biochemical details of the MEP pathway. The research team, in collaboration with Prof. Franck Borel’s group at the University of Grenoble, focused on IspD, an enzyme involved in one of the crucial steps of the MEP pathway. IspD plays a pivotal role in converting precursor molecules into isoprenoid products, making it an ideal target for drug design.
The researchers were able to solve the crystal structure of IspD from P. aeruginosa for the first time, providing them with a detailed understanding of how the enzyme works at a molecular level. By identifying the structure of the enzyme, the team could determine the precise binding sites where small molecules or drug candidates could attach. This understanding was vital in designing new molecules that could interact specifically with IspD.
Through further experimentation, the team synthesized chemical fragments that could bind to IspD with high affinity, blocking its function and disrupting the bacteria’s ability to carry out essential metabolic processes. These fragments serve as a starting point for the development of more complex molecules with even better efficacy and specificity. As project manager Eleonora Diamanti explains, “The fragments we synthesized bind excellently to their target protein IspD, and their other pharmaceutical properties also offer a promising basis for the development of new active ingredients.”
A Novel Approach: IspD as an Unexplored Drug Target
What sets these new drug candidates apart from other antibiotics is the choice of IspD as their target. Current antibiotics primarily focus on well-known bacterial structures, such as the bacterial cell wall or protein synthesis machinery. However, the MEP pathway and IspD enzyme have not been targeted by any existing drugs, making this a novel approach in antibiotic development.
Hirsch emphasizes the importance of this uniqueness, stating that targeting a protein like IspD could help in the development of antibiotics that remain effective against bacteria resistant to conventional treatments. By focusing on this previously unexplored target, Hirsch’s team is aiming to create antibiotics that can tackle a broad spectrum of bacterial pathogens, including those that have already developed resistance to multiple drugs.
This novel approach to antibiotic design represents a significant step forward in overcoming the challenges posed by antibiotic resistance. It offers a targeted strategy for disrupting bacterial metabolism while avoiding the damaging side effects that traditional broad-spectrum antibiotics often inflict on the human body.
Ongoing Development and Future Collaborations
The promising results from Hirsch’s research team have laid a solid foundation for the development of new antibiotics based on IspD inhibition. However, much work remains to be done before these new molecules can become viable treatments for bacterial infections. The next steps involve conducting further efficacy studies in bacterial models, optimizing the compounds for better performance, and refining their pharmaceutical properties, such as bioavailability and toxicity profiles.
One of the key elements driving this research is the collaboration between various research institutions. Prof. Hirsch’s team is set to work closely with the excellence cluster nextAID³, a research initiative focused on exploring new therapeutic targets, including proteins like IspD. The continued collaboration between HIPS, Saarland University, and international partners will be crucial in moving these innovative drug candidates from the laboratory to real-world applications.
“The unique nature of the MEP pathway as a bacterial-specific process opens up new avenues for the development of antibiotics that could overcome many of the challenges posed by antibiotic-resistant pathogens,” says Hirsch. As the global threat of antibiotic resistance continues to grow, such innovative approaches hold the potential to provide new, effective treatments for bacterial infections that were previously difficult or impossible to treat.
Reference: Daan Willocx et al, Fragment Discovery by X‐Ray Crystallographic Screening Targeting the CTP Binding Site of Pseudomonas Aeruginosa IspD, Angewandte Chemie International Edition (2024). DOI: 10.1002/anie.202414615
