Microbiological toxicology of the new antibiotic aditoprim on human intestinal microbiota

Area of Science:

• Microbiology
• Pharmacology
• Toxicology

Background:

• Aditoprim (ADP) is a novel dihydrofolate reductase inhibitor with potent antibacterial activity, low toxicity, and no mutagenicity.
• Its potential applications in human medicine warrant investigation into its effects on the human gut microbiota.

Purpose of the Study:

• To investigate the impact of Aditoprim (ADP) on human intestinal microbiota composition and function.
• To assess the microbiological safety of ADP in an in vitro human gut model.

Main Methods:

• Human intestinal flora were exposed to varying concentrations of ADP (0, 1, 16, 128 mg/L) in chemostats.
• Microflora communities, short-chain fatty acids (SCFAs), antibiotic resistance, and colonization barrier integrity were monitored.
• 16S rRNA sequencing was used to analyze changes in microbial composition, with Salmonella Typhimurium inoculation assessing gut barrier function.

Main Results:

• Long-term exposure to higher ADP levels (16 and 128 mg/L) disrupted the intestinal flora's colonization barrier and increased resistant bacteria.
• Significant alterations in gut microbiota composition were observed at high ADP concentrations, notably affecting Bacteroides fragilis and Bacteroides uniformis.
• The no observable adverse effect concentration (NOAEC) for ADP was determined to be 1 mg/L.

Conclusions:

• Aditoprim (ADP) can disrupt human gut microbiota and compromise the colonization barrier at high concentrations.
• A microbiological acceptable daily intake (MADI) of 91.67 µg/kg.BW/day was established based on the NOAEC.
• ADP demonstrates microbiological safety at concentrations up to 1 mg/L, suggesting a potential therapeutic window.