Epigenetics—the study of heritable changes in gene expression that do not involve alterations to the underlying DNA sequence—is a burgeoning field with potential implications for understanding antimicrobial resistance (AMR). While genetic mutations and horizontal gene transfer are well-established mechanisms by which bacteria acquire resistance, emerging research suggests that epigenetic mechanisms may also influence bacterial responses to antibiotics. Exploring these mechanisms, such as DNA methylation and non-coding RNA molecules, could help scientists develop new strategies to combat AMR.
In bacteria, DNA methylation involves the addition of a methyl group to specific nucleotide bases, often adenine or cytosine, by DNA methyltransferases. This modification can affect DNA replication, repair, and gene expression. While the primary role of DNA methylation in bacteria is associated with restriction-modification systems and regulation of gene expression during cell cycle and virulence, some studies suggest that changes in DNA methylation patterns may influence the expression of genes related to antibiotic resistance.
For instance, DNA methylation may regulate genes encoding efflux pumps—proteins that expel antibiotics from the bacterial cell—and genes involved in biofilm formation, which can shield bacterial communities from antibiotic penetration. Alterations in methylation patterns could potentially modulate these resistance mechanisms, although the extent of this effect is still under investigation.
Although bacteria do not possess histones like eukaryotic cells, they have histone-like proteins (e.g., HU, H-NS) that play roles in DNA organisation and gene regulation. The modification of these proteins and their impact on bacterial gene expression is an area of ongoing research, but their direct role in AMR remains to be fully elucidated.
Non-coding RNAs, including small RNAs (sRNAs), also contribute to gene regulation in bacteria. These molecules can modulate gene expression post-transcriptionally and may influence the expression of antibiotic resistance genes. Understanding how sRNAs affect resistance mechanisms could provide new insights into bacterial adaptation to antibiotic stress.
Investigating epigenetic mechanisms in bacteria opens the possibility of novel approaches to combat AMR. By targeting bacterial DNA methyltransferases or other epigenetic regulators, it might be possible to alter the expression of resistance genes, making bacteria more susceptible to antibiotics. However, this is a nascent field, and significant challenges remain.
For example, inhibiting bacterial DNA methyltransferases could have broad and unintended effects on bacterial physiology, potentially affecting essential cellular processes. Additionally, the redundancy and complexity of bacterial regulatory networks may limit the effectiveness of such strategies.
Researchers are also exploring how environmental factors influence epigenetic modifications in bacteria. Stress conditions, including exposure to sub-lethal concentrations of antibiotics, can induce changes in gene expression that may contribute to transient antibiotic tolerance. Understanding these responses could inform the development of treatment regimens that minimise the induction of adaptive resistance mechanisms.
Some studies have examined the role of DNA methylation in bacterial virulence and antibiotic resistance. In Escherichia coli, for instance, DNA adenine methyltransferase (Dam) methylation influences the expression of genes involved in virulence and may indirectly affect susceptibility to certain antibiotics. Research on Mycobacterium tuberculosis has explored DNA methylation patterns to understand gene regulation, though direct links to antibiotic resistance are still being explored.
While these studies highlight the importance of epigenetic mechanisms in bacterial physiology, more research is needed to establish clear connections between epigenetics and AMR and to develop effective therapeutic interventions targeting these pathways.
Epigenetics offers a promising frontier for understanding bacterial adaptation and potentially combating AMR. By delving deeper into the epigenetic regulation of antibiotic resistance genes, scientists may uncover new targets for antimicrobial therapy. However, translating these findings into clinical applications will require extensive research to validate the efficacy and safety of such approaches.
Coupled with the development of novel antibiotics and alternative treatments, exploring epigenetic interventions could be instrumental in addressing the global AMR crisis. Continued collaboration among microbiologists, geneticists, pharmacologists, and clinicians is essential to advance this field. By integrating knowledge of bacterial genetics, epigenetics, and resistance mechanisms, we can develop innovative strategies to safeguard public health.
This article is authored by Saransh Chaudhary, president, Global Critical Care, Venus Remedies Ltd and CEO, Venus Medicine Research Centre.
