Researchers have designed and synthesized analogues of a new antibiotic effective against multiresistant bacteria, opening a new front in the fight against these infections.
Antibiotics are essential drugs in the treatment of a number of bacterial diseases. However, due to continued overuse and misuse, the number of bacterial strains resistant to multiple antibiotics is increasing, affecting millions of people worldwide. The development of new antibacterial compounds that target multiple drug-resistant bacteria is also an active area of research in order to control this growing problem.
A team led by Professor Satoshi Ichikawa from Hokkaido University is working on the development of new antibacterials. Their most recent research, published in the journal Communication Naturedetails the development of an antibacterial compound that is highly effective against the most common multidrug resistant bacteria.
The team worked on a class of antibacterial compounds called sphaerimicines. These compounds block the function of a protein in the bacteria called MraY. MraY is essential for bacterial replication and plays a role in bacterial cell wall synthesis; nor is it a target of currently available commercial antibiotics.
Sphaerimicines are biological compounds and have very complex structures. We sought to design analogues of this molecule that would be easier to manufacture while becoming more effective against MraY, thereby increasing its antibacterial activity. The drug we designed was effective against methicillin resistant Staphylococcus aureus (MRSA) and vancomycin resistant Enterococcus faecium (ERV), two of the most common multi-resistant bacteria. »
Professor Satoshi Ichikawa, Corresponding Author, Hokkaido University
The team analyzed the structures of sphaerimicin A by computational-assisted molecular modeling, and designed and synthesized two sphaerimicin analogs, SPM1 and SPM2. These analogs have been shown to be effective against Gram-positive bacteria.
They then determined the structure of SPM1 bound to MraY. By studying this structure and comparing it to that of related antibacterial agents, they determined how to further simplify the molecules. They succeeded in developing a simpler analog, SPM3, whose activity was similar to SPM1.
In addition to their effectiveness against MRSA and VRE, SPM was also effective against Mycobacterium tuberculosisthe bacterium that causes tuberculosis and which has multidrug-resistant strains.
“Our most important contribution is the construction of the central sphaerimicin backbone, which can be used to develop more antibacterial agents that target MraY and therefore multidrug-resistant strains. Sphaerimicin is the most promising because MraY is also present in Gram-negative bacteria. concluded Ichikawa. Future work will include the optimization of currently developed SPM molecules and the development of sphaerimicin-containing antibiotic combinations to target a wider range of bacteria.