Dual-Functional Antibiotic Adjuvant Displays Potency against Complicated Gram-Negative Bacterial Infections and...

Area of Science:

• Microbiology
• Pharmacology
• Immunology

Background:

• Gram-negative bacterial infections pose significant treatment challenges due to antibiotic resistance and complex infection forms.
• Existing treatments struggle with issues like bacterial persistence, biofilms, intracellular infections, hyperinflammation, and sepsis.

Purpose of the Study:

• To develop and characterize a novel dual-functional antibiotic adjuvant with immunomodulatory properties.
• To investigate the mechanisms of action of the lead adjuvant, D-LBDiphe, against antibiotic-tolerant bacteria and inflammation.

Main Methods:

• D-LBDiphe was designed as a dual-functional adjuvant targeting bacterial infections and inflammation.
• Mechanistic studies involved assessing outer membrane permeabilization, membrane depolarization, and efflux pump inhibition.
• In vivo efficacy was evaluated in mouse models of *P. aeruginosa* infection and LPS-induced inflammation.

Main Results:

• D-LBDiphe potentiated antibiotic efficacy up to ~4100-fold against antibiotic-tolerant bacteria.
• The adjuvant demonstrated efficacy in topical and systemic *P. aeruginosa* infections in mice.
• D-LBDiphe significantly reduced pro-inflammatory cytokines (61.8-79%) by interacting with lipopolysaccharide (LPS).

Conclusions:

• D-LBDiphe exhibits multimodal mechanisms, including membrane perturbation and efflux inhibition, enhancing antibiotic activity.
• The adjuvant possesses significant immunomodulatory properties, reducing inflammation associated with bacterial infections.
• This study validates antibiotic adjuvants as a promising therapeutic approach for complicated bacterial infections and associated inflammation.