In Vivo Activity Profiling of Biosynthetic Darobactin D22 against Critical Gram-Negative Pathogens

Area of Science:

• Microbiology
• Infectious Diseases
• Drug Discovery

Background:

• Naturally occurring darobactins show promise against Gram-negative pathogens.
• Antibiotic resistance necessitates the development of novel therapeutic agents.

Purpose of the Study:

• To evaluate the in vivo efficacy of D22, a synthetic darobactin analogue.
• To assess D22's activity against critical Gram-negative bacterial infections in preclinical models.

Main Methods:

• In vivo testing in murine models for Pseudomonas aeruginosa thigh infection, Escherichia coli peritonitis/sepsis, and urinary tract infection.
• Zebrafish infection model to evaluate efficacy against Acinetobacter baumannii.

Main Results:

• D22 demonstrated significant in vivo activity against key Gram-negative pathogens, including drug-resistant strains.
• Restored survival in zebrafish embryos infected with Acinetobacter baumannii.
• D22 showed superiority over natural darobactin A in vivo.

Conclusions:

• D22 is a potent antibiotic candidate effective in diverse in vivo infection models.
• Darobactins, particularly D22, represent a versatile therapeutic strategy against Gram-negative bacterial infections.
• Favorable safety profile and efficacy support further development of D22 for novel antibiotic creation.