Hope for new antibacterial therapy

With current concerns about antibiotic resistance and the lack of potential new therapies to treat infectious disease, I was interested to read a report in the journal ACS Chemical Biology by a research team in Yale.

The report suggests that altering the cell wall of Staphylococcus aureus could pave the way for developing new therapies with a mechanism of action different to currently available antibiotics.

S aureus is highly pathogenic. Its virulence is due partly to proteins in its cell wall that enable it to interact with human cells and tissues and evade the human immune system. Proteins are normally incorporated into the cell wall of S aureus through the activity of the bacterium’s enzyme sortase A.

The aim of the study was therefore to disrupt the activity of this enzyme to prevent the attachment of proteins to the cell wall. The researchers incubated wild-type S aureus with specially designed low molecular weight substrates for sortase A. One end of these small molecules was engineered to contain a peptide sequence that would be recognised by the bacteria. The result was that the S aureus cell wall was able to incorporate these molecules covalently into its peptidoglycan.

The researchers used a variety of small molecules, including biotin, fluorescein and azide, in their study. Evidence for their incorporation into the bacterial cell wall was demonstrated by a variety of techniques, including epifluorescence and electron microscopy, flow cytometry, mass spectrometry and biochemical cell wall extraction.

In addition, the azide molecules incorporated in the cell wall were used to perform an azide-alkyne reaction on the bacterial cell surface, so providing further evidence that this small foreign molecule could become embedded in the bacterial peptidoglycan.

The Yale team say this is the first example of cell wall engineering of any Gram-positive pathogenic bacteria. They think their work could lead to the development of novel therapies for treating S aureus and other bacterial diseases. Cell wall-incorporated molecules could be used to help attract antibodies that occur naturally in the bloodstream so increasing the immune response to infectious disease.

The technique may also offer the possibility of engineering organisms with novel functions and could complement ongoing efforts in synthetic biology. This strategy could also be used to label bacteria to watch the progression of disease.

This study follows another piece of work published earlier this year (2010) in Science, which showed that plectasin, a small protein molecule derived from fungi, can destroy some antibiotic resistant bacteria. Plectasin binds to one of the bacterial cell wall precursors, lipid II, preventing it from being incorporated into the cell wall.

According to the European team undertaking this study, plectasin has a mode of action similar to vancomycin. Bacterial strains now resistant to vancomyin are still susceptible to plectasin, although, as the researchers conclude, it is likely only a matter of time before the pathogens mutate and become insensitive.