A Gram-negative-selective antibiotic that spares the gut microbiome

Area of Science:

• Microbiology
• Infectious Diseases
• Drug Discovery

Background:

• Gram-negative bacterial infections are a growing global health concern.
• Current broad-spectrum antibiotics disrupt the gut microbiome, increasing risks of secondary infections.
• There is an urgent need for selective antibiotics targeting pathogens over beneficial bacteria.

Purpose of the Study:

• To design and discover a novel antibiotic with Gram-negative specificity.
• To develop a microbiome-sparing therapeutic agent.
• To establish a blueprint for future antibiotic development.

Main Methods:

• Design of lolamicin targeting the bacterial lipoprotein transport system.
• Testing lolamicin against over 130 multidrug-resistant Gram-negative clinical isolates.
• Evaluation of lolamicin efficacy in mouse models of pneumonia and septicemia.
• Assessment of lolamicin's impact on the gut microbiome and C. difficile colonization.

Main Results:

• Lolamicin demonstrated activity against a wide range of multidrug-resistant Gram-negative bacteria.
• The antibiotic proved effective in preclinical mouse models of infection.
• Lolamicin preserved the gut microbiome in mice, preventing secondary Clostridioides difficile infections.
• The drug's selectivity is attributed to target sequence homology differences between pathogens and commensals.

Conclusions:

• Lolamicin is a novel Gram-negative-specific antibiotic with broad-spectrum activity.
• This antibiotic effectively treats infections while sparing the gut microbiome.
• The selective targeting strategy of lolamicin provides a new paradigm for developing microbiome-sparing antibiotics.