Precision molecule against Gram-negative infections: a new era of antibiotics that spare the gut microbiota

Infections caused by Gram-negative bacteria (sidenote: Gram-negative bacteria A group of bacteria characterized by their unique cell wall structure, which makes them resistant to many antibiotics and often more challenging to treat. ) are becoming more common and are often treated with broad-spectrum antibiotics, which can disrupt the gut microbiome and lead to secondary infections. There is a pressing need for antibiotics that are selective for pathogenic Gram-negative bacteria while sparing commensal bacteria and the gut microbiome.

This new study ¹ aimed to design and discover a Gram-negative-selective antibiotic that targets the Lol lipoprotein transport system, thereby preserving the gut microbiome and preventing secondary infections.

Crafting a selective antibiotic

The development process began with a series of whole-cell screens at AstraZeneca, identifying compounds that inhibit the LolCDE complex, a critical component of the Lol system. Researchers prioritized compounds that showed initial promise but faced challenges in solubility and resistance. Through an iterative chemical modification process, they engineered a hybrid scaffold, appending primary amines to enhance compound accumulation and targeting efficiency.

The culmination of these efforts was the identification of lolamicin (sidenote: Lolamicin A newly developed Gram-negative-selective antibiotic that targets the Lol lipoprotein transport system, effectively killing pathogenic bacteria without disrupting the gut microbiome. ) , a compound that effectively disrupts the Lol system, thereby selectively killing pathogenic Gram-negative bacteria. This selective targeting is made possible by the significant sequence homology divergence between pathogenic bacteria and commensal gut bacteria, ensuring that beneficial bacteria remain unharmed.

Achieving breakthrough results in infection models

The efficacy of lolamicin was put to the test in rigorous preclinical studies, and the results were nothing short of groundbreaking. Lolamicin demonstrated potent activity against a diverse panel of over 130 multidrug-resistant (sidenote: Multidrug-resistant Describes bacteria that have developed resistance to multiple classes of antibiotics, making infections caused by these bacteria particularly difficult to treat. ) clinical isolates of Gram-negative bacteria, including notorious pathogens such as E. coli, Klebsiella pneumoniae, and Enterobacter cloacae.

One of the standout features of lolamicin is its microbiome-sparing capability. Unlike broad-spectrum antibiotics that wreak havoc on the gut microbiome, lolamicin treatment resulted in minimal changes to the gut microbial composition. This was evidenced by full-length 16S rRNA sequencing of fecal samples from treated mice, which showed that lolamicin preserved the diversity and richness of the gut microbiome. Remarkably, mice treated with lolamicin retained their ability to spontaneously clear Clostridioides difficile colonization, a common and severe complication associated with antibiotic use.