Researchers have discovered a breakthrough method to silence MRSA’s drug resistance, restoring its sensitivity to standard antibiotics and offering new hope in the fight against superbugs.
Bacteria methicillin-resistant Staphylococcus aureus MRSA, multidrug resistant bacteria, on surface of skin or mucous membrane, 3D illustration
A study from the Nanjing University School of Life Sciences has revealed a promising new strategy for combating antibiotic-resistant bacterial infections. Researchers have demonstrated that exosomes can successfully deliver small interfering RNA (siRNA) into bacteria, silencing genes responsible for drug resistance. Their findings, published in Cell Reports Medicine, mark a significant step towards treating multidrug-resistant bacteria, a growing global health crisis.
Antibiotic resistance is one of the most pressing challenges in modern medicine, with methicillin-resistant Staphylococcus aureus (MRSA) being one of the most notorious superbugs. Traditional antibiotics are often ineffective against MRSA due to its expression of penicillin-binding protein 2a (PBP2a), encoded by the mecA gene. This new study suggests that the siRNA-Argonaute 2 (AGO2) complex can inhibit mecA translation, potentially rendering MRSA susceptible to conventional antibiotics once again.
Exosomes as delivery vehicles for siRNA therapy
Historically, RNA interference (RNAi) has been limited to eukaryotic cells, as bacteria lack the necessary RNA-induced silencing complex (RISC). However, the researchers have devised an innovative approach using exosomes – small vesicles secreted by cells – to deliver AGO2-bound siRNA directly into bacterial cells. Once inside, the siRNA specifically targets and silences the mecA gene at the translational level, rather than by degrading the mRNA as typically seen in mammalian cells. The ability to suppress gene translation in bacterial cells, despite the absence of traditional RNAi machinery, is a significant breakthrough.
siMecA-AGO2 complex inhibits the translation of the mecA gene which encodes the penicillin-binding protein 2a (PBP2a), a protein at the heart of the drug-resistance phenotype in MRSA. By reducing PBP2a levels by exosome-delivered siMecA-AGO2 complex, MRSA can be converted into methicillin-sensitive bacteria. Thus, coadministration of methicillin (i.p.) and siMecA-Exos (i.v.) effectively protected mice from lethal infection (70% survival rate).
The siMecA-AGO2 complex inhibits the translation of the mecA gene, which encodes penicillin-binding protein 2a (PBP2a) – a key driver of drug resistance in MRSA. By reducing PBP2a levels through exosome-delivered siMecA-AGO2, MRSA can be converted into methicillin-sensitive bacteria. Consequently, coadministration of methicillin (i.p.) and siMecA-Exos (i.v.) effectively protected mice from lethal infection, achieving a 70 percent survival rate. Credit: Cell Reports Medicine
Turning MRSA into a treatable infection
The research team designed a specific siRNA, dubbed siMecA, to target the mecA gene. By delivering siMecA via exosomes, they successfully reduced PBP2a levels in MRSA, effectively converting it into methicillin-sensitive S. aureus (MSSA). This allowed previously resistant bacteria to be treated with standard methicillin-based antibiotics.
In laboratory experiments and in vivo mouse models, the combination of exosome-delivered siMecA-AGO2 (siMecA-Exos) and methicillin treatment resulted in a remarkable 70 percent survival rate among mice infected with lethal MRSA strains. This provides strong evidence that the approach could be a viable therapeutic option for antibiotic-resistant infections in humans.
Potential for clinical applications
One of the most exciting aspects of the study is the potential for in vivo siRNA production. The researchers demonstrated that injecting a plasmid encoding the siRNA into mice prompted the liver to produce exosomes loaded with siMecA-AGO2, which then targeted MRSA infections naturally. This strategy could pave the way for a novel approach to treating bacterial infections without relying solely on synthetic antibiotics.
These findings could have broader implications beyond MRSA. If further research supports the effectiveness of this method against other multidrug-resistant bacteria, it could revolutionise the way we combat bacterial infections.
Moreover, the study raises intriguing questions about whether mammalian cells naturally use exosomes to communicate with and regulate bacterial populations. “It is intriguing to consider the possibility that mammalian hosts employ exosomes to transport molecules with biological functions to the mammalian microbiome for interspecies communication and regulation under physiological conditions,” the authors noted.
As antibiotic resistance continues to threaten global health, innovative solutions like exosome-mediated siRNA therapy offer new hope. Further studies and clinical trials will be crucial in determining whether this novel approach can be adapted for widespread medical use.
This study was published in Cell Reports Medicine.