Visualising Targets for Novel Antibiotics
Globomycin inhibits LspA
Researchers at Oxford, Trinity College Dublin, Diamond and the University of East Anglia have visualised, in high definition, proteins that are essential to bacterial survival, and are therefore potential targets for novel antibiotics.
Indeed one of these proteins is so important that a species of bacteria designed a natural antibiotic, globomycin, as a weapon to kill its competitors, by binding to this protein.
The protein in question is the membrane protein, LspA: a key enzyme in both gram-negative bacteria, like E. coli, where resistance is rapidly on the rise, and gram-positive bacteria like the infamous MRSA and and multi-drug resistant tuberculosis.
The Lipoprotein Pathway
Martin Caffrey’s group at Trinity College Dublin, in collaboration with Dr Phill Stansfeld in the Department of Biochemistry, University of Oxford, have perceived and studied how globomycin binds to LspA.
The study, which is published in the journal Science, provides a means to design new drugs that are similar to globomycin, thereby paving the way for the development of novel antibiotics to kill the resistant and infectious bacteria in the future.
Globomycin works by preventing the correct development of ‘bacterial lipoproteins’. These proteins perform critical roles in behaviour, pathogenicity, and antibiotic resistance of bacteria. Processing of these proteins requires the LspA enzyme to cleave part of the protein, whilst other enzymes in the pathway attach the proteins to the outside of the cell through fatty anchors.
The BAM Complex
An example lipoprotein complex is LptDE, which is essential for the formation of the bacterial outer membrane. The first structure of this complex was reported in Nature in 2014 by Chanjiang Dong’s group, at University of East Anglia, with Dr Phill Stansfeld a key component of the collaboration.
The same team have now solved and assessed another essential lipoprotein complex, called BAM, which is also reported in Nature. This protein is crucial to the insertion of proteins into the outer membrane. Once inserted, these proteins permit the entry of nutrients into the bacterial cell, and also pump out hazardous compounds, such as antibiotics.
Disruption of both complexes therefore provides another route to the development of new antimicrobial agents.
LspA – the processing enzyme for lipoproteins, inhibited by the antibiotic Globomycin:
BAM – responsible for inserting proteins into the bacterial outer membrane:
LptDE – the protein that constructs the bacterial outer membrane: