A technique to screen a diverse range of potential drug candidates without time-consuming purification steps could enhance the battle against drug-resistant bacteria.
Efforts to address the growing challenge of drug-resistant bacteria are being supported by a novel approach to simplify the search for antimicrobial drug candidates, pioneered by researchers at Hokkaido University, under the guidance of Assistant Professor Kazuki Yamamoto and Professor Satoshi Ichikawa from the Faculty of Pharmaceutical Sciences. Their innovative techniques, developed in collaboration with researchers in Japan and the USA, are detailed in a publication in the journal Nature Communications.
The rise of antimicrobial resistance (AMR) in bacteria presents a significant and escalating problem for global healthcare, leaving medical professionals grappling with the treatment of a wide array of severe and potentially life-threatening infections.
One promising target for new drugs to combat various drug-resistant bacteria is an enzyme known as phospho-N-acetylmuramoyl-pentapeptide-transferase (MraY), which is embedded in bacterial cell membranes. This enzyme is crucial for bacterial survival as it catalyzes the formation of a specific lipid molecule, called lipid I. While there are already several inhibitors of MraY activity, there is an urgent need for enhanced versions.
“In our research, we utilized four known classes of MraY inhibitors that are currently employed as antibiotics,” explains Yamamoto. “We established a drug discovery platform (in situ build-up library method) that integrates a comprehensive synthesis technique for derivatives of natural products and direct assessment of biological activity.”
The team divided the known inhibitors into MraY binding cores and activity modulating accessories. From 7 cores and 98 accessories, they created a library of 686 MraY inhibitor analogs. These analogs were evaluated against MraY, leading to the identification of eight compounds with potent MraY inhibitory and antibacterial properties.
“Following the division of natural products, we attached aldehyde groups to the cores and hydrazine groups to the accessories. These groups react with each other to form a hydrazone bond, enabling us to generate the analog library efficiently,” elaborates Yamamoto.
The eight analogs were remade in stable forms and their efficacy was confirmed. Among them, Analog 2 exhibited the highest effectiveness against drug-resistant strains, followed by Analogs 3 and 6. Analog 2 also demonstrated effectiveness in mouse infection models, indicating a promising feature as showing efficacy in live animals is a critical step towards the development of successful new drugs.
Preliminary findings also suggest that the potential candidate drugs identified thus far exhibit low toxicity against cells other than the targeted bacteria, raising optimism that they could pave the way for a series of antimicrobial agents that are safe for patient use.
“Furthermore, we showcased the broader applicability of our drug discovery method by utilizing it to identify beneficial activity in tubulin-binding natural products like epothilone B, paclitaxel, and vinblastine (used in anticancer drugs),” adds Ichikawa. “We were able to construct a library of 588 analogs within just one month.”
By demonstrating that their approach can be extended to other medication classes, the researchers have opened up a significantly broader pathway in drug development.
