Authors: Aimee RP Tierney and Philip Rather
Take a look behind the scenes of a recent Future Microbiology review, entitled ‘Role of two-component regulatory systems in bacterial antibiotic resistance’, as we ask the authors about the mechanisms of two-component regulatory systems and what potential these could hold for drug development.
What inspired you to write this piece?
The widespread emergence of antimicrobial resistance is likely to be the largest healthcare crisis of this century, both in terms of human mortality and economic impacts. While this problem is certainly multifaceted and requires intervention on many fronts, such as drug development, innovative healthcare practices and better stewardship, all attempts to combat this crisis must begin with a better understanding of bacterial cell biology and regulation.
What are bacterial two-component regulatory systems? Why are these important for bacterial antibiotic resistance?
Two-component regulatory systems are signal transduction systems through which bacteria sense changes in their environment and respond in ways that benefit and protect the cell. Many two-component systems sense environmental or structural changes caused by antibiotic action and can thereby allow a cell to avoid deleterious effects through enacting transcriptional changes that counteract the antibiotic’s mechanism of action.
What are some example mechanisms by which these systems elicit resistance?
Some two-component regulatory systems bring about remodeling of the cell surface, such as the outer membrane or cell wall, prohibiting direct action by antibiotics such as colistin and vancomycin. Many systems elicit changes in cell permeability to halt diffusion of drug into the cell or increase drug efflux. Still others are capable of directly sensing a specific antibiotic and activating transcription of enzymes that degrade it.
How can we use this understanding to combat resistance?
Understanding the cellular mechanisms that underlie resistance is crucial in predicting the countermeasures and evolutionary pathways a bacterial species is likely to take in evading an antibiotic. It further stands to reason that increasing our knowledge of the systems that guide bacterial interpretation of their surroundings, including the presence of antibiotics, is critical. With this information, we may be able to design antibiotics that take advantage of these systems by targeting those essential for resistance or cell function, or perhaps even activating cellular changes that increase vulnerability to other drugs or phage therapy.
What work are you hoping to do? What do you think needs to be done in this area?
Targeting two-component regulatory systems and understanding their many capabilities offers several potential benefits to drug development. Research in bacterial genetics that explores these systems at a fundamental level will be essential, as well as studies that use genomics to reveal the presence of orthologous resistance-promoting two-component systems in previously overlooked pathogens. We should also seek to better understand the exact condition(s) or ligand(s) that activate many types of two-component systems, which at present are not well-defined for many systems. Finally, analyses that define the three-dimensional structures of these proteins and identify molecules that act antagonistically to their functioning will be necessary to develop new antibiotics and synergistic drugs.