Credit: by freepik

On May 29th, the journal Nature published a research report on a new antibiotic named lolamicin, conducted by a research team from the University of Illinois at Urbana-Champaign. According to the article titled "A Gram-negative-selective antibiotic that spares the gut microbiome," lolamicin is a broad-spectrum antibiotic capable of eliminating Gram-negative bacteria resistant to multiple antibiotics without disrupting the gut microbiome.

What are Gram-negative Bacteria?

Gram-negative bacteria are a class of bacteria characterized by a unique cell wall structure that renders them Gram-negative under Gram staining. This class includes various pathogenic bacteria, such as Klebsiella pneumoniae, Escherichia coli, and Neisseria gonorrhoeae. These bacteria can cause a range of diseases, from mild food poisoning to severe cholera and sepsis. Due to their distinctive cell wall structure and multiple defense mechanisms, Gram-negative bacteria naturally resist many antibiotics.

The outer membrane of Gram-negative bacteria contains lipopolysaccharides (LPS), which enhance their defensive capabilities and can trigger strong immune responses. Additionally, these bacteria possess efficient drug efflux pumps and enzymes capable of hydrolyzing antibiotics, making many antibiotics ineffective.

Antibiotic resistance presents another major challenge with Gram-negative bacteria. Through gene mutations and horizontal gene transfer (such as plasmid transfer), these bacteria quickly acquire and disseminate resistance genes, complicating treatment efforts. Multidrug-resistant (MDR) Gram-negative bacteria are particularly concerning as they resist most conventional antibiotics, leaving only a few effective drugs, which often have significant side effects or limited efficacy.

credit:https://doi.org/10.1038/s41586-024-07502-0

Confocal microscopy of (a) E. coli BW25113; lolamicin-resistant mutants, (b) BW25113 LolC-N265K, (c) BW25113 LolE-D264N; (d) K. pneumoniae ATCC 27736; and lolamicin-resistant mutants, (e) LolC-Q258L and (f) LolE-V59L. Scale bar is 10 µm. Antibiotics were tested at the following concentrations (3X MIC or just below the solubility limit for lolamicin in resistant mutants): E. coli—DMSO 2%; lolamicin 8 µg/mL for E. coli BW25113, 64 µg/mL for resistant strains; globomycin 24 µg/mL; mecillinam 0.4 µg/mL; aztreonam 0.1 µg/mL. K. pneumoniae—DMSO 2%; lolamicin 3 µg/mL for K. pneumoniae ATCC 27736 or 64 µg/mL for resistant strains; globomycin 64 µg/mL; mecillinam 3 µg/mL; aztreonam 1.5 µg/mL. Cell size (n = 25) in E. coli (g) and K. pneumoniae (h) and resistant mutants was quantified. Length and width were measured in ImageJ and cell area calculated using the area formula for an ellipse (A = π*ab where a = ½ length and b = ½ width). Measurements were compared using two-sample Welch’s t-test (one-tailed test, assuming unequal variance). NS, not significant (P > 0.05); *** (P < 0.0005). E. coli BW25113: lolamicin (P = 3.44 × 10−18), globomycin (P = 1.00 × 10−15); E. coli BW25113 LolC-N265K: lolamicin (P = 0.28), globomycin (P = 4.16 × 10−10); E. coli BW25113 LolE-D264N: lolamicin (P = 0.09), globomycin (P = 4.44 × 10−12). K. pneumoniae ATCC 27736: lolamicin (P = 3.59 × 10−17), globomycin (P = 3.22 × 10−16); K. pneumoniae ATCC 27736 LolC-Q258L: lolamicin (P = 0.22), globomycin (P = 1.26 × 10−8); K. pneumoniae ATCC 27736 LolE-V59L: lolamicin (P = 0.24), globomycin (P = 2.59 × 10−11).

Emergence of a New Antibiotic

The research team from the University of Illinois at Urbana-Champaign identified lolamicin, a Gram-negative bacteria-specific antibiotic, by screening and modifying a series of compounds. Lolamicin targets the lipoprotein transport system (Lol system), a protein complex found exclusively in Gram-negative bacteria. By inhibiting this system, lolamicin selectively kills pathogenic bacteria without harming non-pathogenic ones. The team’s experiments showed that lolamicin is effective against 130 drug-resistant strains.

In mouse models of acute pneumonia and sepsis, lolamicin demonstrated significant therapeutic effects. All mice infected with antibiotic-resistant bacteria survived after receiving lolamicin treatment, while 87% of untreated mice died within three days. These results highlight lolamicin's potential in treating multidrug-resistant infections.

Impact on Gut Microbiome

The research team specifically examined lolamicin's impact on the gut microbiome. Common broad-spectrum antibiotics like amoxicillin severely disrupt the gut microbiome, leading to Clostridioides difficile infections. C. difficile is an opportunistic pathogen that proliferates when the gut microbiome is imbalanced, causing severe diarrhea and colitis, which can be life-threatening.

In contrast, lolamicin exhibits high selectivity, targeting only Gram-negative pathogens and sparing beneficial gut bacteria. Experimental results indicated that mice treated with lolamicin maintained normal gut microbial diversity and structure, whereas those treated with conventional broad-spectrum antibiotics showed significant microbial imbalance.

Lolamicin not only excels in treating primary infections but also prevents secondary infections caused by gut microbiome disruption. The research team found that lolamicin effectively prevented C. difficile overgrowth. Mice treated with lolamicin experienced almost no secondary infections from C. difficile, further proving lolamicin's advantages in preserving gut health.

Prospects and Challenges

Despite these promising experimental results, translating the success of targeting the Lol system in Gram-negative bacteria from mice to a human-usable drug is a long and complex journey. Developing antibiotics is a lengthy process, often exceeding 20 years from discovery to clinical approval. Additionally, the economic returns from developing new antibiotics are not substantial, leading to underinvestment by pharmaceutical companies in this field.

Over the past decade, about 10-20 new antibiotics targeting Gram-negative bacteria have been discovered, yet none have received approval from the US Food and Drug Administration (FDA). While this research provides a new direction for future antibiotic development, it also reminds us of the persistent challenges in combating bacterial infections.

The discovery of lolamicin undoubtedly injects new hope into antibiotic research. By targeting bacterial-specific systems rather than broad-spectrum killing, lolamicin represents a more refined and intelligent antibiotic development strategy, potentially offering safer and more effective treatment options for patients in the future.

Reference：

1.Muñoz, K.A., Ulrich, R.J., Vasan, A.K. et al. A Gram-negative-selective antibiotic that spares the gut microbiome. Nature (2024). https://doi.org/10.1038/s41586-024-07502-0

2.https://www.nature.com/articles/s41586-024-07502-0