Infectious diseases have posed significant health challenges throughout human history. While the advent of antibiotics and other antimicrobials was aimed to address this concern, the persistent and widespread use of these agents has led to the emergence of antimicrobial resistance (AMR) and numerous multiple drug-resistant organisms (MDROs).

AMR occurs when bacteria, virus, fungi and parasites change over time and no longer respond to existing treatments.  In 2019 the World Health Organization (WHO) described it as one of the top ten global threats to public health – a threat to which science is playing catch-up in its efforts to mitigate.

Close to 5 million lives are lost annually due to drug-resistant infections.2 Projections suggest that without intervention, global deaths attributable to AMR could reach 10 million by 2050 (the same as cancer deaths).3 In addition to high mortality and morbidity, the economic toll of AMR is substantial. In fact, the World Bank estimates that AMR could result in US$ 1 trillion additional healthcare costs by 2050, and US$ 1 – $3.4 trillion gross domestic product (GDP) losses per year by 2030.4

Mechanisms of Antimicrobial Resistance

The biochemical and genetic mechanisms that cause AMR, fall into four categories: inactivation of the antimicrobial molecule; target modification; active drug efflux; and drug uptake limitation. These mechanisms are summarized below and in Table 1.

• Inactivation of Antimicrobial Molecules: Microorganisms produce enzymes that deactivate drugs by either destroying them or adding specific chemical components, rendering the antimicrobial ineffective at its target site. These modifying enzymes, catalyzing reactions like acetylation, phosphorylation, and adenylation, induce steric hindrance, diminishing the drug’s affinity for its target and raising the bacterial Minimum Inhibitory Concentration (MIC). β-lactam resistance exemplifies this, employing β-lactamases to break amide bonds in the β-lactam ring, rendering the antimicrobial ineffective. Over 1000 β-lactamases have been identified, with more expected as bacterial evolution continues.

• Target Modification is a key resistance mechanism involving alterations to the antimicrobial target site, impeding proper binding of the antimicrobial molecule. These sites are crucial for cellular functions during antimicrobial action. Mutational changes on the target site can reduce inhibition susceptibility while preserving essential cellular functions. In some cases, inducing resistance through modifying target structures may require additional cellular changes. An example is the acquisition of penicillin-binding transpeptidase (PBP2a) in methicillin-resistant Staphylococcus aureus.
• Active Drug Efflux: Efflux pumps, found in families like the major facilitator superfamily (MFS), small multidrug resistance family (SMR), resistance-nodulation cell division family (RND), ATP-binding cassette family (ABC), and multidrug and toxic compound extrusion family (MATE), have the capacity to expel antimicrobial agents rapidly from the bacterial cell. This expulsion mechanism significantly contributes to multidrug resistance.
• Drug Uptake Limitation: Bacteria vary in their ability to limit drug uptake. The outer membrane composition in organisms like gram-negative bacteria slows antimicrobial penetration. Mycobacteria’s lipid-rich outer membrane hinders hydrophilic drug entry. Organisms lacking a cell wall, such as Mycoplasma, are inherently resistant to cell wall-targeting agents. Biofilm formation protects against immune system attacks and provides defense against antimicrobial agents.

Origins of Antimicrobial Resistance

Microorganisms demonstrate genetic plasticity, enabling them to evolve resistance mechanisms against environmental threats, including antimicrobial agents. The development of antimicrobial resistance involves various processes:

1. Mutational Resistance: Susceptible microbial populations undergo mutations in genes affecting drug activity, facilitating cell survival in the presence of antimicrobial agents.
2. Spontaneous Mutations: Random mutation events, arising from replication errors or incorrect DNA strand repairs, contribute to antimicrobial resistance.
3. Hypermutations: Certain bacterial populations enter transient states of elevated mutation rates under prolonged non-lethal antibiotic pressure. Mutators in this context confer selective advantages.
4. Adaptive Mutagenesis: Mutations occur in slowly dividing or non-dividing cells under non-lethal selective pressure, leading to the development of resistant mutants.
5. Horizontal Gene Transfer (HGT): Bacterial evolution is influenced by the acquisition of foreign materials through HGT mechanisms, such as transformation, conjugation, and integrons. These processes contribute to the development of antimicrobial resistance.

Addressing Antimicrobial Resistance through Metagenomic Next Generation Sequencing 

Metagenomic Next-Generation Sequencing (mNGS) provides unbiased, culture-independent diagnosis and surveillance of resistance mechanisms. Recognized as an indispensable tool, mNGS provides a complete genomic sequence and unparalleled structural detail on individual traits within a population, which contributes to more reliable microbial identification, definitive phylogenetic relationships, and a comprehensive catalog of traits. Additionally, mNGS can also be used for outbreak investigations, microorganism-agnostic infectious disease diagnosis, especially for novel pathogens and appropriate treatment selection.   

Understanding the mechanisms and origins of antimicrobial resistance is crucial in developing effective strategies to mitigate its impact.  Learn how our Pathogen Real-Time Identification by Sequencing (PaRTI-Seq™) complete mNGS assay provides rapid and accurate identification of resistant pathogens and invaluable insights for the management of AMR.  (https://micronbrane.com/products/)

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