Researchers headed by a team at Hokkaido University have designed and synthesized a sphaerimicin analog antibacterial that targets an essential bacterial enzyme, MraY, and which was found to be effective against multidrug-resistant (MDR) bacteria. The team says their work could potentially open the way to the development of new drugs against drug-resistant resistant bacterial strains.
“Sphaerimicins are biological compounds, and have very complex structures,” explained research lead Satoshi Ichikawa, PhD. “We set out to design analogs to this molecule that would be easier to manufacture while also becoming more effective against MraY, thus increasing its antibacterial activity. The drug we designed was effective against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VRE), two of the more common multi-drug resistant bacteria.”
Ichikawa is lead author of the team’s published paper in Nature Communications, which is titled “Synthesis of macrocyclic nucleoside antibacterials and their interactions with MraY.” In their report the investigators concluded, “Our study combines synthetic chemistry, structural biology, and microbiology to provide a platform for the development of MraY inhibitors as antibacterials against drug-resistant bacteria.”
Antibiotics are vital drugs for treating a number of bacterial diseases. However—and partly as a result of continuing overuse and misuse—the number of bacterial strains that are resistant to multiple antibiotics is increasing, affecting millions of people worldwide, such that “bacterial antimicrobial resistance (AMR) poses a severe threat to human health worldwide,” the authors wrote. The team cited figures suggesting that 1.27 million deaths worldwide in 2019 were attributable to AMR. “In order to address AMR, the development of new antibacterial drugs with novel mechanisms of action is urgently needed,” they stated.
More than half of the 162 antibacterial drugs approved by FDA over the last 40 or so years have been natural products and their derivatives, “indicating the important role of natural products in antibacterial drug discovery,” the researchers continued. It can, however, can be difficult to synthesize natural products due to their chemical complexity. “Therefore, designing simplified analogues that retain activity is an important objective in the medicinal chemistry of natural products.”
The Hokkaido University team has been working on the development of new antibacterials, including sphaerimicins. These compounds block the function of the bacterial protein MraY, which plays a role in the synthesis of the bacterial cell wall, and is essential for bacteria replication. As the investigators noted, MraY is not a target of currently available commercial antibiotics. “ … conventional antibacterial agents do not act on MraY, which makes it an attractive target for drug-resistant bacterial drugs,” they stated.
For their newly reported study the scientists analyzed structures of sphaerimicin A by molecular modelling, assisted by calculation, and then they designed and synthesized two analogs of sphaerimicin, SPM-1 and SPM-2. “As the first step, we predicted a stereoisomer of a sphaerimicin skeleton with potent MraY inhibitory activity out of the eight possible stereoisomers, assisted by molecular modeling, and then designed SPM-1 and SPM-2,” they wrote. Tests showed that these two analogs were effective against Gram positive bacteria.
The researchers then determined the structure of SPM-1 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 then used this knowledge to develop a simpler analog, SPM-3, which demonstrated activity similar to that of SPM-1. “Our structural and biological analyses revealed that the stereochemistry of the macrocyclic core of the SPMs is critical for inhibitor potency,” the team explained. “The insight obtained from these studies allowed us to execute the second step drug design of SPM-3, which is chemically more accessible while retaining similar potency.”
Tests showed that in addition to their effectiveness against MRSA and VRE, the SPMs were also effective against Mycobacterium tuberculosis, the bacterium that causes tuberculosis—which also has multidrug-resistant strains. “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,” Ichikawa stated. “Sphaerimicin is most promising as MraY is also present in Gram negative bacteria.”
Future work will include optimisation of the currently developed SPM molecules, and the development of sphaerimicin-containing antibiotic combinations to target a wider range of bacteria. The authors concluded, “The macrocyclic skeleton found in this study and its detailed molecular interaction with MraY, provide a scaffold for developing potent MraY inhibitors, which could be promising leads for antibiotics against drug-resistant bacteria.”