A New Promising Anti-Infective Agent Inhibits Biofilm Growth by Targeting Simultaneously a Conserved RNA Function...

Area of Science:

• Microbiology
• Drug Discovery
• Biofilm Research

Background:

• Single and multi-drug-resistant bacterial infections, particularly in biofilms, pose a significant global health challenge.
• Innovative therapeutic targets and novel chemical compounds are urgently needed to overcome existing resistance and prevent future strains.
• T-box genes, crucial for amino acid metabolism and cell viability in Gram-positive bacteria, represent a promising, host-absent target.

Purpose of the Study:

• To identify and develop novel compounds that effectively inhibit bacterial biofilm formation and combat drug-resistant organisms.
• To evaluate the efficacy of PKZ18-22, a T-box regulatory element inhibitor, against *Staphylococcus aureus* biofilms.
• To assess the synergistic potential of PKZ18-22 with existing antibiotics.

Main Methods:

• In silico screening of 305,000 molecules to identify T-box gene inhibitors, leading to the PKZ18 compound family.
• Synthesis and testing of PKZ18 analogs, with a focus on PKZ18-22 for potency and mechanism of action.
• Comparative analysis of PKZ18-22 efficacy against *S. aureus* biofilms versus vancomycin.
• Evaluation of PKZ18-22 in combination with gentamicin and rifampin for synergistic effects.

Main Results:

• PKZ18-22 demonstrated significant potency, being 10-fold more effective than vancomycin in inhibiting *S. aureus* biofilm growth.
• PKZ18-22 effectively inhibits the T-box regulatory mechanism, halting essential gene transcription and leading to bacterial cell death.
• The compound exhibited synergistic effects when combined with existing antibiotics like gentamicin and rifampin.
• Inhibition of T-box genes by PKZ18-22 proved effective regardless of bacterial growth state (planktonic or biofilm).

Conclusions:

• PKZ18-22 is a highly potent inhibitor of T-box regulatory elements, offering a novel strategy against antibiotic-resistant *Staphylococcus aureus* biofilms.
• The compound's ability to disrupt essential gene transcription and its synergistic potential with other antibiotics highlight its promise for clinical applications.
• Targeting T-box genes provides a viable approach to combatting current drug-resistant strains and preventing the emergence of new resistant bacteria.