Accelerating the discovery of antibacterial compounds using pathway-directed whole cell screening

Area of Science:

• Microbiology
• Pharmacology
• Drug Discovery

Background:

• The rise of antibiotic resistance threatens global health, necessitating novel therapeutic strategies beyond traditional monotherapies.
• Compound combinations, including those targeting virulence or resistance factors, are emerging as promising alternatives to combat resistant pathogens.
• High-throughput screening (HTS) is crucial for identifying new drug leads, but traditional methods can be slow and inefficient.

Purpose of the Study:

• To introduce a novel pathway-directed high-throughput screening paradigm.
• To overcome limitations of traditional target-based and whole-cell screening methods.
• To discover new compounds for combination therapies against antibiotic-resistant bacteria, specifically methicillin-resistant Staphylococcus aureus (MRSA).

Main Methods:

• Development and application of a pathway-directed HTS paradigm.
• Integration of advantages from target-based and whole-cell screening approaches.
• Screening for inhibitors of specific bacterial pathways, including d-alanylation.

Main Results:

• The pathway-directed HTS paradigm enables rapid identification of biologically active compounds.
• Successful identification of a new class of d-alanylation inhibitors.
• Demonstrated utility in discovering compounds for combination therapies.

Conclusions:

• The developed screening paradigm efficiently identifies potent antimicrobial compounds.
• The newly discovered d-alanylation inhibitors show potential for combination therapies against MRSA.
• This approach accelerates the discovery of novel treatments for antibiotic-resistant infections.