The Gel-ous Antibiotic


Breaking down the microbiology world one bite at a time

The Gel-ous Antibiotic

Every year, antimicrobial-resistant infections kill over 1.27 million people worldwide. This forces scientists and healthcare workers to devise novel strategies that combat or work around such resistance. 

Ideally, we discover new antibiotics each time some bacteria become resistant to their previous treatment(s). Unfortunately, that outcome remains unrealistic and unsustainable. In reality, we consider ourselves fortunate if we find one antibiotic that could treat a single bacterial infection. Oftentimes, scientists rely on other methods, like bacteriophages, to address resistant infections. 

This makes a discovery, similar to the one in our chosen study, especially promising. It revolves around a newer antibiotic and its prodrug analogues — specifically O-acyl isopeptide prodrug analogues. The newer antibiotic refers to teixobactin, while its prodrug analogues refer to structurally-similar medicinal substances. These substances change within our body before they affect us. 

Different teixobactin analogues and O-acyl isopeptide prodrugs structures. 
Source: Chelsea R. Jones et al (2022)

Teixobactin itself works against gram positive bacteria. Gram positive bacteria contain 3 main components in their cell walls: peptidoglycan, teichoic acid, and lipid. Teixobactin binds to this lipid (specifically lipid II plus other precursors for cell wall constituents). 

These binding sites lie outside the cell, immune to change — which significantly lowers the risk of resistance. It seems foolproof except for one thing: 

Teixobactin gels once it enters physiological conditions (think pH, temperature, etc.). 

This makes teixobactin’s route of administration (intravenous injection) nearly impossible. The gelation also contributes to teixobactin’s potency, which renders our antibiotic useless through any other medium or modification. 

Such circumstances have prompted researchers to investigate teixobactin’s prodrug analogues. The researchers in this study demonstrate how teixobactin’s O-acyl isopeptide prodrug analogues, particularly linkages, evade our gelation issue. 

Recall that prodrugs only start to work or take an active form after they enter our bodies. The O-acyl isopeptide linkages experience delayed gelation, i.e., they gel relatively little pre-intravenous administration. Afterwards, everything gels as necessary. 

This way, we can get our drug therapy into a patient such that it retains its antibiotic potency. Researchers have also measured, then characterized, different factors like kinetics to support the aforementioned conclusion. Additionally, they have demonstrated that O-acyl isopeptide linkages work against the gram-positive methicillin-resistant staphylococcus infection (MRSA), or staph, in a live mouse thigh model — with negligible cytotoxicity.

Overall, bacterial infections like MRSA, vancomycin-resistant enterococcus (VRE), and several more continue to threaten us everyday. Increased antibiotic resistance only exacerbates matters since it strains hospitals further while they deal with residual effects from the COVID-19 pandemic. Teixobactin O-acyl isopeptide prodrug analogues show significant promise for future drug therapy as they offer hope during these infectious times.

Link to the original post: Jones, C. R., Guaglianone, G., Lai, G. H., & Nowick, J. S. (2022). Isobactins: O-acyl isopeptide prodrugs of teixobactin and teixobactin derivatives. Chemical Science, 13(44), 13110-13116

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