New approaches to tackling antibiotic-resistant bacteria
Antibiotics are not used just to treat simple infections. Complex medical interventions – such as chemotherapy, organ transplants and heart surgery – also rely heavily on the efficacy of these drugs. “It is critical that we make good use of the antibiotics we have,” explains ChronosAntibiotics project coordinator Mariana Pinho from NOVA University Lisbon in Portugal. “Given time, bacteria have an incredible capacity to develop resistance to virtually all antibiotics.” This is one reason why developing new antibiotics is so challenging and costly. A key concern is that a promising new drug could quickly become obsolete due to resistance. For many new compounds, pharmaceutical companies make the call that conducting expensive and time-consuming clinical trials is simply not worth it.
Efficient new ways of screening antimicrobials
The ChronosAntibiotics project, which was supported by the European Research Council, sought to address this clinical challenge with a two-pronged approach. The first aim was to better understand how bacteria divide. The project team focused on the bacterium Staphylococcus aureus (S. aureus), a clinical pathogen. “If we understand how a pathogen divides, then we can start to think of novel ways to prevent its division during an infection,” adds Pinho. The project began by screening S. aureus genes with fluorescence microscopy and using machine learning to automatically analyse cells. “This allowed us to determine the cell cycle stage of tens of thousands of cells, and to identify specific mutants that are impaired in cell cycle progression,” says Pinho. “We then studied the biological role of the proteins that are missing in each mutant. This enabled us to uncover new mechanisms of cell cycle regulation, as well as previously unknown proteins required for correct chromosome segregation. These are critical for bacteria to survive inside an infected host.”
Analysing compounds to inhibit bacterial growth
The second aim of the project was to develop more efficient ways of screening antimicrobial compounds, based on a better understanding of cellular bacterial processes. The team developed bacterial strains that become fluorescent in the presence of compounds designed to inhibit bacterial growth. “We wanted to construct strains that respond to the presence of a certain class of antibiotics, or to the inhibition of a metabolic pathway that we might want to target,” explains Pinho. “This might include inhibiting cell wall synthesis, fatty acid biosynthesis or DNA synthesis.” Pinho and her team believe that these bacterial strains could lead to more efficient screening and study of potential new antibiotics.
Understanding biology of pathogens
On the first aim, Pinho believes that the project has made a valuable contribution to a critically important area of clinical healthcare. “Learning about the biology of pathogens always matters,” she says. “I cannot be certain that our findings will directly accelerate antibiotic discovery. However, if we don’t try to better understand these organisms, we will limit our ability to develop new antimicrobial strategies.” On the second aim, Pinho notes that the screening technology needs to be further optimised. Nonetheless, she hopes that this innovation will eventually lead to the discovery of new antimicrobial compounds. “Another long-term legacy of this project will be the new scientists that were trained during this project,” she adds. “Our hope is that they will continue to work on this topic, and eventually lead their own labs.”
Keywords
ChronosAntibiotics, bacterial, biology, drugs, antimicrobial, antibiotics