Researchers have developed an antibacterial compound that is effective against multidrug resistant bacteria. The study, published in Nature Communications, combined a synthetic chemistry, structural biology and microbiology approach to develop inhibitors of a bacterial enzyme that is not currently targeted by available antibiotics.
We need new antibiotics
Antimicrobial resistance is a looming problem. Bacteria are becoming increasingly resistant as antibiotics continue to get misused and overused. As a result, new compounds that have different modes of action and can also target multidrug resistant bacteria are imminently required.
Researchers, led by Professor Satoshi Ichikawa at Hokkaido University, developed antibacterial compounds that target a bacterial protein that that is currently not a target of available antibiotics. The compound was effective against common multidrug resistant bacteria.
The researchers explored a class of antibacterial compounds called sphaerimicins. These compounds, which have complex macrocyclic structures, are naturally occurring inhibitors of a bacterial enzyme called MraY. MraY is essential for cell wall synthesis, so it is a promising target for antibacterial compounds. Unfortunately, the complex structure of sphaerimicins makes it difficult to develop them as antibacterials.
Satoshi Ichikawa, corresponding author and Professor at Hokkaido University said, “Sphaerimicins are biological compounds, and have very complex structures. We set out to design analogues to this molecule that would be easier to manufacture while also becoming more effective against MraY, thus increasing its antibacterial activity.”
Synthetic chemistry + structural biology + microbiology = effective antibacterials
The researchers analysed and reconstructed the macrocyclic structure of sphaerimicin A using molecular modelling. They designed and synthesised two compounds that had a similar molecular structure to sphaerimicin A: SPM1 and SPM2. The compounds were effective against Gram-positive bacteria.
The researchers then aimed to simplify the structure of the SPM1 sphaerimicin A analogue. They analysed the structure of SPM1 and other related antibacterial agents bound to the target protein MraY (figure 1). They then used a structure-guided approach to design simplified analogues. This led to the development of a third compound, called SPM3, which had a similar level of antibacterial activity to SPM1.
The researchers showed that the SPM compounds were effective against three important multidrug resistant bacteria: methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium and Mycobacterium tuberculosis.
Renewed hope in the fight against multidrug resistant bacteria
The study shows that MraY is promising antibacterial target that can be explored as a target for other multidrug resistant bacteria.
Professor Ichikawa said, “Our most significant contribution is the construction of the core skeleton of sphaerimicin, which can be used to develop more antibacterial agents that target MraY and hence multidrug-resistant strains. Sphaerimicin is most promising as MraY is also present in Gram-negative bacteria.”