The Last Line of Defense: A One Health Perspective on the Spread, Molecular Mechanisms, and Novel Strategies of Last-Resort Drug Resistance

The rise of antimicrobial resistance (AMR) poses an existential threat to modern medicine, with resistance to last-resort agents signaling a potential post-antibiotic era. These ultimate therapeutics, including polymyxins, carbapenems, and oxazolidinones, are our final defense against multidrug-resistant pathogens. Their erosion compromises the success of critical interventions like chemotherapy, organ transplantation, and major surgery. Crucially, resistance to these agents transcends human healthcare, it is fueled by a complex interplay of factors across the human-animal-environment interface, following the pathways of the One Health triad. Understanding this interconnected spread, unravelling the sophisticated molecular mechanisms driving resistance, and innovating novel diagnostic, therapeutic, and stewardship strategies are therefore not just a research priority but a global health imperative.

These drugs, our ultimate line of defense against the most resistant bacterial pathogens, are failing at an alarming rate. The problem is inherently multidimensional. From a One Health perspective, the drivers of resistance are interconnected and pervasive: the overuse and misuse of these critical agents in human medicine, their widespread application in animal agriculture, and their persistent release into the environment create a continuous cycle of selection pressure and resistance gene dissemination. This crisis is compounded by a profound scientific and translational gap: while new resistance mechanisms (e.g., novel mcr genes, evolving carbapenemases) emerge rapidly, our understanding of their precise molecular mechanisms, evolutionary trajectories, and true prevalence across different One Health reservoirs remains incomplete. Consequently, the development and implementation of novel counter-strategies, including next-generation diagnostics, alternative therapies, and effective stewardship policies are critically lagging.

We encourage submissions on, but not limited to, the following scope:
1. Molecular mechanisms and genetic determinants underlying resistance to last-resort drugs (e.g., carbapenems, polymyxins, oxazolidinones, tigecycline).
2. Comparative studies on resistance among critical-priority pathogens, including CRE, CRAB, MRSA, and VRE.
3. Epidemiology and transmission pathways of resistance across the One Health continuum.
4. Plasmid-mediated or mobile genetic element-driven dissemination of resistance genes.
5. Innovation and evaluation of novel diagnostics, alternative therapies, or antimicrobial stewardship strategies targeting last-resort resistance.

Article types and fees

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Editorial
• FAIR² Data
• FAIR² DATA Direct Submission
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• Original Research
• Perspective
• ... View all formats

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Article types

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Editorial
• FAIR² Data
• FAIR² DATA Direct Submission
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• Original Research
• Perspective
• Review
• Systematic Review
• Technology and Code

Keywords: one health, last-resort drugs, antimicrobial resistance, humans, animals, environment, resistance determinants, epidemiology, resistance mechanisms, novel strategies

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.