The Rise of Plasmid-Mediated Resistance in Mycobacteria: A Looming Threat
For decades, tackling Mycobacterium abscessus and other rapidly growing mycobacteria (RGM) involved navigating a complex landscape of intrinsic and acquired antibiotic resistance. But a new chapter is unfolding, driven by the increasing prevalence of resistance genes carried on plasmids – mobile genetic elements capable of rapidly spreading through bacterial populations. Recent research, including studies by Brown-Elliott et al. (2024, 2025) and Alexander et al. (2025), is revealing the extent of this threat and its implications for treatment strategies.
The Plasmid Problem: How Resistance is Spreading
Traditionally, antibiotic resistance in mycobacteria was thought to arise primarily from chromosomal mutations. However, the discovery and characterization of plasmids carrying resistance genes, particularly those conferring resistance to macrolides, have dramatically shifted this understanding. Plasmids, unlike chromosomal DNA, can be transferred between bacteria – even across species – through a process called conjugation. This horizontal gene transfer accelerates the spread of resistance, making infections harder to treat.
The erm gene family, responsible for macrolide resistance, is a key player. Researchers have identified novel variants like erm(41) (Nash et al., 2009) and erm(55) (Brown-Elliott et al., 2024) residing on plasmids. These genes modify bacterial ribosomes, preventing macrolide antibiotics from binding and halting bacterial protein synthesis. The emergence of broad-host-range plasmids, capable of transferring between diverse mycobacterial species, is particularly concerning (Diricks et al., 2025).
Pro Tip: Understanding the mechanisms of resistance is crucial for developing new therapeutic strategies. Targeting plasmid replication or conjugation could potentially slow the spread of resistance.
Beyond Macrolides: A Wider Resistance Landscape
While macrolide resistance is currently the most prominent plasmid-mediated threat, the potential for other resistance genes to hitch a ride on these mobile elements is significant. Historically, plasmids have carried genes conferring resistance to mercury (Meissner & Falkinham, 1984; Schué et al., 2009) and other heavy metals in mycobacteria, demonstrating their capacity to harbor diverse resistance determinants. The recent identification of conjugative plasmids in Mycobacterium marinum (Ummels et al., 2014) and other species suggests a broader reservoir of transferable resistance genes exists.
The presence of toxin-antitoxin (TA) systems on these plasmids (Díaz-Orejas et al., 2017; Yang & Walsh, 2017) further complicates matters. TA systems often stabilize plasmids, ensuring their maintenance within bacterial populations, and can even contribute to the spread of resistance by providing a selective advantage to bacteria carrying the plasmid.
The Role of Genomics and Advanced Sequencing
Unraveling the complexities of plasmid-mediated resistance requires sophisticated genomic tools. Whole-genome sequencing (WGS), coupled with long-read sequencing technologies like those from Oxford Nanopore (Hickman & Rapid, 2024), is becoming increasingly essential. These technologies allow researchers to accurately assemble complete bacterial genomes, including plasmids, and identify resistance genes with greater precision.
Bioinformatics pipelines like Hybracter (Bouras et al., 2024) and Unicycler (Wick et al., 2017) are streamlining the process of genome assembly, while tools like MAFFT (Katoh & Standley, 2013) and MEGA11 (Tamura et al., 2021) facilitate the analysis of resistance gene sequences. The ability to rapidly characterize resistance plasmids is critical for tracking their spread and informing clinical decisions.
Future Trends and Potential Solutions
Several trends are likely to shape the future of plasmid-mediated resistance in mycobacteria:
- Increased Prevalence: Continued monitoring will likely reveal a further increase in the prevalence of resistance plasmids, particularly in clinical settings.
- Novel Resistance Genes: The discovery of new resistance genes carried on plasmids is inevitable, requiring ongoing surveillance and adaptation of treatment protocols.
- Enhanced Conjugation: Factors influencing conjugation rates, such as environmental conditions and bacterial population dynamics, will need to be investigated to understand how resistance spreads. Research suggests environmental strains may be more adept at receiving plasmids (Shoulah, 2018).
- Development of Novel Therapeutics: The need for new antibiotics and alternative therapies, such as bacteriophage therapy or CRISPR-based approaches, will become increasingly urgent.
- Improved Diagnostics: Rapid diagnostic tests capable of detecting resistance plasmids will be crucial for guiding treatment decisions and preventing the spread of resistant strains.
Did you know? The ability of plasmids to transfer between different bacterial species highlights the importance of a One Health approach to antimicrobial resistance, recognizing the interconnectedness of human, animal, and environmental health.
Frequently Asked Questions (FAQ)
Q: What are plasmids?
A: Plasmids are small, circular DNA molecules that exist separately from a bacterium’s chromosomal DNA. They can carry genes that confer antibiotic resistance and are capable of transferring between bacteria.
Q: Why is plasmid-mediated resistance so concerning?
A: Plasmids can spread resistance genes rapidly between bacteria, even across species, making infections harder to treat and potentially leading to widespread antibiotic resistance.
Q: What is being done to combat this threat?
A: Researchers are using advanced genomic technologies to track the spread of resistance plasmids, identify new resistance genes, and develop novel therapeutic strategies.
Q: How does whole genome sequencing help?
A: WGS allows scientists to identify the complete genetic makeup of a bacterium, including any plasmids present and the resistance genes they carry.
This evolving landscape demands a proactive and collaborative approach. Continued research, coupled with responsible antibiotic stewardship, is essential to mitigate the threat of plasmid-mediated resistance and protect public health.
Explore further: Read our article on Antibiotic Stewardship Best Practices to learn how you can help combat antibiotic resistance.
