Developing antibiotics that target multiple-drug-resistant bacteria
The sphaerimicin analogs (SPMs) inhibit the activity of MraY, and hence the replication of bacteria, with different degrees of effectiveness. The potency of the analog increases as the IC50 decreases. Credit: (Takeshi Nakaya, et al. Nature Communications. December 20, 2022)

There is a new front in the fight against infections that are resistant to drugs created by researchers.

Antibiotics are used to treat a number of infections. Millions of people around the world are affected by the increasing number ofbacteria strains that are resistant to multiple antibiotics. The development of new antibacterial compounds that target multiple drug resistantbacteria is an active field of research that can be used to control the issue.

Professor Ichikawa leads a team at Hokkaido University that is working on the development of new antibiotics. Their most recent research, published in the journal Nature Communications, describes the development of a highly effective antibacterial compound that is effective against the most common multidrug-resistantbacteria.

There is a class of compounds called srimicins. The function of MraY is blocked by these compounds. MraY is not a target of antibiotics currently on the market.

Ichikawa explained that sphaerimicins have very complex structures. We designed analogs that would be easier to make and more effective against MraY, in order to increase its antibacterial activity. We designed a drug that was effective against two of the most common multi-drug resistantbacteria.

The team analyzed the structures of srimicin A and designed and synthesised two analogs. The analogs were found to work against Gram positivebacteria.

The structure of MraY was determined by them. They were able to simplify the molecule by studying it and comparing it to other antibacterial agents. They were able to develop a simpler analog called SPM3.

The SPMs were also effective against the bacterium that causes Tuberculosis, as well as multidrug-resistant strains.

The construction of the core skeleton of sphaerimicin can be used to develop more antibacterial agents that target MraY and therefore multidrug resistant strains. Ichikawa said that Sphaerimicin is most promising as MraY is in Gram negativebacteria. The development of antibiotic combinations to target a wider range ofbacteria will be included in the future.

There is more information about the synthesis of macrocyclic nucleoside antibacterials and their interactions with MraY.

Journal information: Nature Communications