Breaking down the microbiology world one bite at a time

The good antibiotic

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You may have heard a lot about the pros and cons of antibiotics – lately, more cons than pros. Antibiotics if taken when absolutely necessary and with complete dosage are good. But, if taken in the absence of necessity and with haphazard dosage, the same antibiotics spread their wrath. How so?
The antibiotics in the market either target gram-positive bacteria or both gram-negative and gram-positive bacteria (broad spectrum antibiotics), making little discrimination between the commensals– the usual inhabitants of the human gut, and the pathogens– the unusual or opportunistic inhabitants. This leads to antibiotics wiping down most of the gut bacterial population, even the ones that help humans by breaking down compounds that they can’t otherwise. In addition, the rampant consumption of antibiotics has led to the spread of antibiotic resistance genes across many parts of the world.

You may think that the world is done with antibiotics while praying that an occasional bacterial infection resolves itself. Alas, this is not always the case and we have definitely not heard the end of antibiotics. Yet another diva is in town. But this time with a twist that can save the commensals.

Lolamicin – the new diva of antibiotics

A recent study describes a gram-negative specific antibiotic –Lolamicin – that does not target all gram-negatives, but rather mostly the pathogenic ones. To understand its strategy, let’s dive into how antibiotics target bacteria. Antibiotics target bacterial proteins or their complexes that are essential for bacteria’s survival. For gram-negatives, the complex membrane structure and efflux pumps make the job of antibiotics difficult. Therefore, broad spectrum antibiotics affect the peptidoglycan crosslinks of all bacteria, but this as we know wipes away most gut microbes. It is not that the gram-negative specific antibiotics have not been tested before. But the ones before Lolamicin targeted the outer membrane which was effective only for gram-negatives that have compromised permeability. Therefore, the current antibiotics in the market for the gram-negatives do not impact the pathogens with intact permeability.

Besides the outer membrane, another potential target of antibiotics is the periplasmic space, between the outer membrane and the inner membrane beyond which the cytoplasm lies. Lolamicin targets the lol system. It is a 5-component protein system responsible for the lipoprotein transport between the inner and outer membranes in the gram-negative. For context, the gram-positives’ lipoproteins are entirely attached to their cytoplasmic membrane and therefore they don’t need this lipoprotein system. Whereas in many ESKAPE gram-negative pathogens, this system is highly conserved, with low sequence similarity to gram-negative commensals. Here lies the opportunity for Lolamicin to attack only the gram-negative pathogens.

Lolamicin action in cell membranes of gram-negative and gram-positive bacteria. Image created by author in libre-office using pictures from wikipedia and RSCB-PDB

Among the 5 components of lol, 3 form a complex LolCDE, required for transporting outer membrane specific lipoproteins from the inner membrane. The authors focused on the LolCDE complex and developed Lolamicin against this complex. Previously, AstraZeneca identified two types of compounds that can inhibit the LolCDE complex, namely pyridinepyrazoles and pyridinemidazoles. However, these compounds could not be used as drugs because of the lack of robust evidence for their antimicrobial activity against gram-negative pathogens. The authors of the current study tweaked and optimized the chemical structures of these compounds, finally developing Lolamicin.

Efficacy and impact of Lolamicin

The authors performed extensive tests with Lolamicin on gram-negatives and gram-positives as well as, aerobes and anaerobes, and compared their results with other antibiotics like Clindamycin and Amoxicillin. They found that Lolamicin selectively targeted E. coli, K. pneumoniae, and E. cloacae, sparing the gut commensals. On the other hand, Clindamycin and Amoxicillin targeted pathogens as well as commensal bacteria like the Bacteroides, which is a well-known commensal across human gut microbiome profiles.

The authors also studied the impact of Lolamicin on the gut microbiome of healthy mice. They found that the overall diversity of the gut microbiome in mice treated with Lolamicin remained unaltered compared to the mice treated with control compounds (vehicle). On the other hand, mice treated with Clindamycin and Amoxicillin showed a drastic change in microbial diversity and led to an increase in certain bacterial families and phyla.

Cautious interpretation

While this research opens new avenues for selective gram-negative targeting antibiotics, much more investigation is needed before it can be used as a drug for humans. The long-term impact of previously developed antibiotics became evident only gradually, partly because questions around microbial evolution were not efficiently addressed. Microbes evolve rapidly, and their genomes change in response to their immediate surroundings. For earlier antibiotics, such genomic changes led to drastic outcomes, like the acquisition of antibiotic resistance genes, which were discovered long after these drugs were first used. Today, scientists understand microbial evolution better and frequently conduct experiments to assess how any drug can alter the microbial genome. Lolamicin will need to undergo many such experiments before it can join the ranks of effective antibiotics.

Link to the original post: Muñoz, K.A., Ulrich, R.J., Vasan, A.K. et al. A gram-negative-selective antibiotic that spares the gut microbiome. Nature 630, 429–436 (2024). https://doi.org/10.1038/s41586-024-07502-0

Featured image: Image created by author in libre-office using pictures from wikipedia and RSCB-PDB