Provide a Number of Promising Starting Points for Developing New Classes of Antibiotics
These molecular compounds have potent antibacterial activity against a broad spectrum of Gram-negative bacteria, have no structural similarity to known antibiotics, can be readily synthesized in a few steps, and have low cytotoxicity with mammalian cells. Antibiotic resistance is an increasing world problem, mostly due to the overuse and misuse of antibiotics. With more than 2 million hospital-acquired infections in America occurring yearly and ~23,000 deaths due to resistant pathogens, the cost to our society and health care system runs in the range of tens of billion dollars per year. The estimated cost of treatment of a single patient infected with antibiotic-resistant bacteria is more than $20,000. Existing antibiotics target few specific pathways, leaving gaps for resistance to develop, and current predictions indicate antibiotic resistance is usually observed within 2 years of marketing a new antibiotic. Consequently, the need for antibiotic development centered on new mechanisms of drug action and/or new drug target classes is urgent.
Researchers at the University of Florida have developed a large-scale, ultra-high throughput screening strategy that leverages automation to assay the biological and biochemical activities of more than 645,000 unique compounds. This ultra-high throughput screening has identified 19 small molecule compounds for use in inhibiting bacterial growth and treating bacterial infections. The identified compounds have been proven to be more effective antibiotics against a wide range of gram-negative bacteria such as Pseudomonas aeruginosa when compared to treatment with existing antibiotics. These small molecule compounds are extremely useful because their diverse chemical structures can be leveraged for further development into broad-spectrum antibiotics.
Application
Molecular compounds that represent a starting point to develop new classes of antibiotics with modes of action different from those available now
Advantages
- Demonstrate potent antibacterial activity against a broad spectrum of Gram-negative bacteria, providing a starting point for developing new classes of antibiotics
- Have low cytotoxicity with mammalian cells, ensuring the resulting antibiotics are not only effective but safe for clinical use
- Encompasses molecules with 8 structural classes with no similarity to existing antibiotics, underscoring the potential to target numerous bacterial pathways that are different from pathways targeted by currently available antibiotics
- Includes molecules that have been benchmarked across clinically relevant Gram-negative and Gram-positive bacteria, highlighting their broad-spectrum application
Technology
Ultra-high-throughput screening is used to rapidly test many compounds against a specific target, such as antibacterial activity. Researchers at the University of Florida have employed a large-scale, ultra-high throughput screening approach to identify compounds in the Scripps Drug Discovery Library (SDDL) with potential antibiotic activity. These compounds were tested for safety using mammalian cell-based assays to ensure they were not toxic to human cells. Out of the initial compounds, compounds with toxicity, high reactivity, poor drug-likeness, pan-assay interference issues, and similarity to existing antibiotics were eliminated, leaving about 19 readily available hits. The 19 resulting molecules have the potential to serve as building blocks for new classes of antibiotics with unique modes of action, which will serve to mitigate the current prevalence of antibiotic resistance associated with available antibiotics.
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