Unconventional Antibacterials and Adjuvants.

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Microbiology

Background:

• The diminishing pipeline of new antibiotics and the rise of resistant bacteria necessitate novel therapeutic strategies.
• Traditional antibiotic discovery methods have slowed, requiring innovative approaches to combat bacterial infections.

Purpose of the Study:

• To present three distinct laboratory strategies for discovering novel antibacterial agents and adjuvants.
• To identify new classes of non-β-lactam inhibitors and antibacterial adjuvants using computational and experimental methods.

Main Methods:

• Targeted discovery of non-β-lactam inhibitors for penicillin-binding proteins (PBPs), leading to oxadiazoles and quinazolinones.
• Investigation of allosteric regulation of cell-wall biosynthesis, focusing on PBP2a of *Staphylococcus aureus*.
• Exploration of regulatory phosphorylation events and revisiting bulgecins as β-lactam potentiators.

Main Results:

• Identified oxadiazoles and quinazolinones as novel antibacterial classes targeting PBPs.
• Elucidated the allosteric regulation of PBP2a and demonstrated binding of quinazolinones and ceftaroline to this site.
• Discovered picolinamides as antibacterials and identified three classes of antibacterial adjuvants.
• Confirmed bulgecins potentiate β-lactam antibiotics by inhibiting lytic transglycosylase Slt, leading to bacterial lysis.

Conclusions:

• The developed strategies have yielded promising small-molecule antibacterials and adjuvants.
• These findings offer new therapeutic avenues for treating challenging bacterial infections.
• The identified compounds, including oxadiazoles, quinazolinones, picolinamides, and bulgecins, represent valuable leads for future drug development.