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Researchers have made significant strides in identifying new antimicrobial drugs from bacterial datasets, offering potential alternatives to traditional antibiotics. A recent study, published as a Reviewed Preprint in eLife, showcases a novel approach to discovering lysins—enzymes produced by phages during infection—with antimicrobial properties. This breakthrough holds promise for addressing the growing global health threat of antibiotic resistance.
Antibiotic resistance occurs when disease-causing microorganisms evolve to withstand treatments that once killed them, posing a severe public health concern. Overuse of antimicrobial agents in humans, livestock, and agriculture has exacerbated this issue. Lysins, derived from phages (viruses that infect bacteria), present a promising alternative due to their low risk of resistance and unique mode of action.
“Lysins have demonstrated antimicrobial effects and are considered a promising alternative to antibiotics,” says lead author Li Zhang, a PhD candidate at Huazhong Agricultural University in Wuhan, China. “However, the discovery of lysins for treating infections is hindered by the limited availability of published phage genome data.”
Zhang and colleagues turned to bacterial proteomes—the entire set of proteins expressed by bacterial genomes—to identify new lysins. They used the well-documented antimicrobial peptide P307 as a template, scanning the proteome database of Acinetobacter baumannii (A. baumannii) to uncover five new lysins with antimicrobial potential: PHAb7-11. Initial tests highlighted PHAb10 and PHAb11 as particularly promising.
The researchers synthesized gene-coding sequences for the five lysins and expressed them in Escherichia coli (E. coli) cells. They tested the lysins against three bacterial species: A. baumannii, Pseudomonas aeruginosa, and E. coli. Even at low concentrations, the lysins exhibited high antibacterial activity.
Further evaluation of PHAb10 and PHAb11 revealed robust antibacterial activity against six bacterial cultures in both stationary and exponential growth phases. Notably, these lysins were effective against antibiotic-resistant strains.
The team also discovered that PHAb10 and PHAb11 maintained significant antibacterial activity after heat treatment at 100°C for one hour, unlike PHAb7, PHAb8, and PHAb9. X-ray crystallography revealed that PHAb10 undergoes a folding-refolding process during heat treatment, enhancing its stability. This thermostability is mediated by seven pairs of intermolecular interactions, similar to a zipper mechanism.
Testing PHAb10 in two mouse models of bacterial infection showed that it safely and effectively cleared the infections, demonstrating its therapeutic potential.
eLife reviewers emphasize the need for further tests, such as live/dead assays, to enhance the robustness of the findings. This method uses fluorescent dyes to differentiate between live and dead bacterial cells, providing greater insight into lysins’ bactericidal effectiveness.
“Our work demonstrates that daily updated big data, such as bacterial genomes and proteomes, could be a crucial tool in the fight against antibiotic resistance,” says senior author Hang Yang, a professor at the Wuhan Institute of Virology, Chinese Academy of Sciences. “We successfully identified new antimicrobial lysins with therapeutic promise. PHAb10 and PHAb11 are highly thermostable lysins with a broad spectrum of antimicrobial action. If future studies validate our findings, these lysins could be explored further as potential therapeutic treatments.”
This innovative approach offers a valuable new strategy for discovering alternatives to traditional antibiotics, marking a significant advancement in combating antibiotic resistance and enhancing global public health.
