Research led by Warwick University has uncovered the mechanism by which the bacterium Streptococcus pneumoniae has become resistant to the antibiotic penicillin, opening up new avenues for the design of antibiotics against resistant bacteria, including the hospital acquired infection, MRSA (Methicillin resistant Staphylococcus aureus).
Penicillin normally acts by preventing the construction of peptidoglycan, an essential component of the bacterial cell wall. This provides a protective mesh around the otherwise fragile bacterial cell, providing the mechanical support and stability.
The research focused on MurM, a protein that has been linked to changes in the chemical make up of peptidoglycan in penicillin resistant Streptococcus pneumoniae. It turns out that MurM is key to the formation of particular structures within S. pneumoniae peptidoglycan called dipeptide bridges. These link together peptidoglycan strands into the mesh that forms the bacterial cell wall. The presence of high levels of these dipeptide bridges in the peptidoglycan of Streptococcus pneumoniae is a pre-requisite for high level penicillin resistance.
The researchers, led by Adrian Lloyd of Warwick’s Department of Biological Sciences along with colleagues from the Université Laval, Ste-Foy in Quebec, and the Rockefeller University, New York, have replicated the activity of MurM in vitro to define the chemistry of the MurM reaction in detail. The results will allow the Warwick team, and any interested pharmaceutical researchers, to target the MurM reaction as a route to disrupting the resistance of S. pneumoniae to penicillin.
The research also offer the possibility of disrupting the antibiotic resistance of MRSA, which uses similarly constructed peptide bridges in its cell wall.
In a further spin-off the researchers are also able to reproduce every precursor step the bacterial cell uses to generate peptidoglycan, generating a collection of targets for antibiotic development.
The Warwick researchers have established a network of academics from the fields of chemistry, biology and medicine, as well as pharmaceutical companies to share and exploit these targets. This is the UK Bacterial Cell Wall Biosynthesis Network (UK-BaCWAN) and it is supported by the UK Medical Research Council of the UK.