Bacterial proteases, untapped antimicrobial drug targets

Area of Science:

• Microbiology
• Biochemistry
• Drug Discovery

Background:

• Bacterial proteases are crucial for bacterial cell viability, stress response, and pathogenicity.
• Despite their potential as antimicrobial targets, no clinically approved drugs currently target bacterial proteases.
• The rise of pan-antibiotic resistance necessitates the exploration of novel therapeutic strategies.

Purpose of the Study:

• To review the potential and recent advancements in developing compounds targeting bacterial proteases.
• To focus on AAA+ family proteolytic complexes, specifically Caseinolytic protease (ClpP), and signal peptidases (SPs) as therapeutic targets.

Main Methods:

• Review of existing literature on bacterial protease inhibitors and activators.
• Focus on chemical perturbation strategies for ClpP and its associated ATPases.
• Examination of successful chemical inhibition of type I and type II signal peptidases (SPs).

Main Results:

• Compounds targeting ClpP can inhibit, activate, or perturb its associated ATPase, offering diverse therapeutic approaches.
• Both type I and type II SPs have been successfully targeted by chemical inhibitors, validating them as viable drug targets.
• Bacterial proteases represent a rich source of novel antibiotic targets.

Conclusions:

• Bacterial proteases, including ClpP and SPs, present significant opportunities for developing novel antibiotics and anti-virulence drugs.
• Targeting bacterial proteases is a viable strategy to combat the growing threat of antibiotic resistance.
• Further development of compounds targeting these enzymes is crucial for future antimicrobial therapies.