Dr. Mavridou on Antibiotic Resistance and Bacterial Proteostasis

Novel Strategy to Tackle Antibiotic Resistance: Dr. Mavridou's research presents a novel approach to combat antibiotic resistance. By targeting a single non-essential bacterial protein, DsbA, the team was able to inhibit multiple antibiotic resistance (AMR) determinants.DsbA and its Role: DsbA, a protein unique to bacteria, plays a significant role in the function of various resistance enzymes. By inhibiting this protein, the research team managed to sensitize certain pathogens to existing antibiotics, making those drugs effective once again.β-lactamase Enzymes and DsbA: A significant focus was placed on β-lactamase enzymes, which confer resistance to a range of antibiotics. By targeting DsbA, these enzymes were incapacitated, especially those that aren't affected by classical β-lactamase inhibitors. This is especially relevant as many clinically important pathogens possess these enzymes.MCR Enzymes and Colistin Resistance: The rise of MCR enzymes has made the antibiotic colistin, often a last-resort drug, less effective. However, since MCR enzymes contain multiple disulfide bonds, inhibiting the DSB system could reverse this resistance.Efflux Pump Inhibitors: There's a notable absence of clinically viable efflux pump inhibitors. While the impact of DsbA on efflux pumps was modest, the relationship between DsbA and pump function was underscored, pointing towards future areas of exploration.Potential of Cell Envelope Proteostasis: The bacterial cell envelope's protein management system has significant untapped potential. The DSB system, once considered merely a maintenance system, is crucial for bacterial adaptation. It's essential for virulence, plays a role in the life cycle of bacterial persister cells, and, crucially, is vital for bacterial survival against antibiotics.Clinical Implications: The study showcases the potential of targeting bacterial proteostasis pathways. Inhibiting such systems in pathogens could lead to more effective treatment methods that neutralize AMR determinants and disarm virulence factors.Conclusion: Dr. Mavridou's research offers a groundbreaking approach to countering antibiotic resistance. By understanding and targeting bacterial proteostasis, especially the DSB system, there's potential to develop novel therapeutic strategies, reinvigorate the efficacy of existing antibiotics, and provide a framework for future antibiotic research.https://doi.org/10.7554/eLife.57974