Hospitals and doctors have been wary of the rapid rise in antibiotic resistance among disease-causing microorganisms. One infamous example is MRSA, methicillin-resistant Staphylococcus aureus. This increase in multidrug-resistant bacteria is a cause for concern globally. Before the discovery of antibiotics, Staphylococcus aureus was fatal in 80% of infected wounds. Antibiotic resistance could yield a future where this horrifying statistic resurfaces.
Antibiotics have played a major role in our progress as a species. It has been estimated that antibiotics have increased average life expectancy in the developed world by as much as 20 years. However, over time, bacteria and other microorganisms have developed a resistance to these drugs through mutation. These new resistant strains of bacteria then pass on their favourable genes either through their clones (binary fission) or via horizontal gene transfer.
New classes of antibiotics can help combat these drug-resistant strains of bacteria, by using novel mechanisms of action which these microorganisms are not resistant to. One such example is Teixobactin (Txb), a new type of antibiotic with a unique chemical scaffold. It is used against Gram-positive bacteria. Teixobactin’s target in a bacterial cell is lipid II, a precursor of peptidoglycan.
The C-terminal headgroup of teixobactin specifically binds to the pyrophosphate-sugar moiety of lipid II, while the N terminus binds the pyrophosphate of another lipid II molecule. This results in the formation of a structure resembling a β-sheet of teixobactins bound to the bacteria, creating a supramolecular fibril-like structure. The pyrophosphate-sugar moiety is conserved in the structure of lipid II, and teixobactin binds to it specifically, leading to a lack of resistance.
The fibrillar supramolecular structure of the teixobactin-bacterial complex affects the integrity of the bacterial membranes by displacing its constituent phospholipids – thinning the membrane. However, both bacterial and human cell membranes are made of phospholipids, so how does teixobactin selectively affect bacterial cells without being toxic to healthy human cells?
Since teixobactin’s mechanism of action relies on the binding of the drug to lipid II, it only acts on cell membranes containing lipid II. Lipid II is absent in eukaryotes, which tackles the potential problem of drug toxicity. The image below summarises teixobactin’s mechanism of disrupting bacterial cell membranes and inhibiting cell wall biosynthesis:
This two-pronged action against cell wall synthesis and the cytoplasmic membrane produces a highly effective compound targeting the bacterial cell envelope. The struggle between antibiotic resistance and drug development is analogous to an arms race. The discovery of antibiotics and the intense reliance on them in the past have pushed bacteria to mutate and evolve to survive these threats. As such, more specific drugs are required to be developed as a countermeasure.
Txb is a step in the right direction to develop more specific and effective drugs in order to counteract resistant strains. Hopefully, there will be many more antibiotics in the future with diverse mechanisms of action to combat bacterial infections.
References
Shukla, R., Lavore, F., Maity, S. et al. Teixobactin kills bacteria by a two-pronged attack on the cell envelope. Nature 608, 390–396 (2022). https://doi.org/10.1038/s41586-022-05019-y
