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Published on: October 12, 2022
Whole-organism phenotypic screening for anti-infectives promoting host health
Anne E Clatworthy1,2,3, Keith P Romano2,4, Deborah T Hung5,6,7
1Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Abstract:
To date, antibiotics have been identified on the basis of their ability to kill bacteria or inhibit their growth rather than directly for their capacity to improve clinical outcomes of infected patients. Although historically successful, this approach has led to the development of an antibiotic armamentarium that suffers from a number of shortcomings, including the inevitable emergence of resistance and, in certain infections, suboptimal efficacy leading to long treatment durations, infection recurrence, or high mortality and morbidity rates despite apparent bacterial sterilization. Conventional antibiotics fail to address the complexities of in vivo bacterial physiology and virulence, as well as the role of the host underlying the complex, dynamic interactions that cause disease. New interventions are needed, aimed at host outcome rather than microbiological cure. Here we review the role of screening models for cellular and whole-organism infection, including worms, flies, zebrafish, and mice, to identify novel therapeutic strategies and discuss their future implications.
Insights
New therapeutic strategies should target host outcomes, not just bacterial killing, to overcome antibiotic resistance and improve patient recovery in complex infections. This approach offers better clinical results than traditional methods.
Area of Science:
- Infectious Diseases
- Microbiology
- Drug Discovery
Background:
- Current antibiotics are selected for bacterial killing, not clinical outcomes, leading to resistance and suboptimal efficacy.
- Conventional approaches neglect complex host-pathogen interactions and in vivo bacterial physiology, contributing to treatment failures.
- There is a critical need for novel therapeutic strategies focused on improving patient outcomes in infectious diseases.
Purpose of the Study:
- To review the utility of screening models for identifying novel therapeutic strategies against infections.
- To discuss the implications of shifting therapeutic targets from microbiological cure to host outcome.
Main Methods:
- Review of cellular and whole-organism infection screening models.
- Inclusion of models such as worms, flies, zebrafish, and mice.
- Analysis of strategies for identifying novel therapeutic interventions.
Main Results:
- Screening models offer a viable platform for discovering therapeutics that improve clinical outcomes.
- These models can address the limitations of traditional antibiotic discovery methods.
- The review highlights the potential of host-directed therapies.
Conclusions:
- Novel interventions should prioritize host outcomes over solely targeting bacterial eradication.
- Screening models are essential tools for developing next-generation anti-infective strategies.
- A paradigm shift towards host-outcome-based drug discovery is necessary for combating infectious diseases effectively.
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