Antimicrobial resistance and mechanisms of epigenetic regulation

Abstract

The rampant use of antibiotics in animal husbandry, farming and clinical disease treatment has led to a significant issue with pathogen resistance worldwide over the past decades. The classical mechanisms of resistance typically investigate antimicrobial resistance resulting from natural resistance, mutation, gene transfer and other processes. However, the emergence and development of bacterial resistance cannot be fully explained from a genetic and biochemical standpoint. Evolution necessitates phenotypic variation, selection, and inheritance. There are indications that epigenetic modifications also play a role in antimicrobial resistance. This review will specifically focus on the effects of DNA modification, histone modification, rRNA methylation and the regulation of non-coding RNAs expression on antimicrobial resistance. In particular, we highlight critical work that how DNA methyltransferases and non-coding RNAs act as transcriptional regulators that allow bacteria to rapidly adapt to environmental changes and control their gene expressions to resist antibiotic stress. Additionally, it will delve into how Nucleolar-associated proteins in bacteria perform histone functions akin to eukaryotes. Epigenetics, a non-classical regulatory mechanism of bacterial resistance, may offer new avenues for antibiotic target selection and the development of novel antibiotics.

Keywords: DNA modification; antimicrobial resistance; epigenetic drugs; epigenetics; non-coding RNAs; rRNA methylation.

Figure 1

Mechanism of antimicrobial resistance and its transmission. Transformation is the intra- and inter- species exchange of naked DNA released by cell lysis or gene sequences actively effluxed by some bacteria. Conjuction is the direct transfer of DNA molecules (such as plasmids) from donor bacteria to recipient bacteria through the pipeline formed by sex pilus. Transduction is the transfer of DNA from donor bacteria to recipient bacteria by bacteriophages (Depardieu et al., 2007; Zhang, 2014; Yuan et al., 2022). Membrane vesicle fusion means that vesicles secreted which includes nucleic acids, enzymes and drug resistance genes and other substances, can enter another bacteria or host cells through direct fusion with host cell membrane or endocytosis (Depardieu et al., 2007; Zhang, 2014; Yuan et al., 2022). The outer membrane porin mediates the entry and exit of antibiotics into and out of bacteria as a permeability barrier. When the porin is missing or reduced, some antibiotics reduce influx and the host bacteria become resistant. The production of antibiotic hydrolases, inactivating enzymes and modifying enzymes can lead to the inactivation of antibiotics. The mutation or modification of related targets makes it impossible for antibiotics to bind to the corresponding sites to play a bactericidal or bacteriostatic role (Depardieu et al., 2007; Zhang, 2014; Yuan et al., 2022).

Figure 2

Position of DNA methylation. Adenine can add methyl at N6. Cytosine can add methyl at either endocyclic (C5) or exocyclic (N4) (Kumar et al., 2018).

Figure 3

DNA phosphorothioation modification simple diagram. Based on R-M system, DNA PT modification recognize and restrict non-PT-protected foreign DNA, such as plasmids. The sulfur is transferred from L-cycsteine to DndA, and then to the cysteine residues in DndC and through DndDE complex protein to insert into the DNA backbone (Tang et al., 2022). DndB function as a negative regulator controlling the expression of dndCDE. DndFGH function as a restriction module to affect the acquisition of exogenous DNA (Wang et al., 2019).

Figure 4

Epigenetic effects on adaptive resistance. When bacteria are continuously exposed to sub-inhibitory concentrations of antibiotics, they undergo adaptive evolution and gradually acquire resistance, which can be inherited. When antibiotics are withdrawn, the bacteria with adaptive resistance phenotype will immediately return to sensitivity (Marinus and Casadesus, 2009; Ghosh et al., 2020). Persistent bacteria are only a small part of the bacterial community that is stunted or slow to grow. Persistent bacteria can survive without mutation when exposed to antibiotic pressure (Marinus and Casadesus, 2009). These indicate that bacterial adaptive resistance is epigenetically regulated.

Figure 5

Overview of the function of bacterial DNA methylation. The R-M systems function as a barrier to recognize host genome and defenses foreign DNA, such as phage, plasmid (Phillips et al., 2019). Unlike R-M systems, orphan methyltransferases exist with no association with any restriction enzymes, and always function as regulators of DNA replication, gene transfer. Particularly, some orphan methyltransferases are not essential for most bacteria (Srikhanta et al., 2009). FinOP system regulates the conjugal transfer operon (tra) of plasmids. Specifically, traJ activates the transcription of tra operon (encodes the elements of pilus and products required for mating and DNA transfer). Synthesis of TraJ is controlled by FinP, a regulator that blocks traJ mRNA translation, and by FinO, a regulator that maintains the stability of FinP RNA-traJ mRNA complex (Jen et al., 2014). Dam methylation function as a conjugation repressor by activating FinP RNA synthesis. During the cell division process in bacteria, the essential FtsZ protein polymerizes into a Z-ring like structure at the future division site (Brockman et al., 2018). MipZ protein, which co-ordinates the initiation of chromosome replication with cell division, is important for the assembly of the Z-ring. MipZ interacts with the partitioning protein ParB, which then binds to the ParS locus near the chromosomal origin (davies, 2003). CcrM methylation activates the transcriptions of ftsZ and mipZ. When lacking the CcrM enzyme, the syntheses of FtsZ protein and MipZ protein are strongly downregulated, leading to a severe defect in cell division. In Caulobacter crescentus ΔccrM strain, most ΔccrM cells are filamentous with high cell length variability and frequent membrane defects (davies, 2003).