From the Guidelines
Antimicrobial resistance (AMR) through alternative metabolic pathways is a significant concern in the treatment of infections, as it allows bacteria to bypass the metabolic processes targeted by antimicrobial drugs, and the most recent evidence suggests that understanding these pathways is crucial for developing new antimicrobials 1.
Mechanisms of Alternative Metabolic Pathways
The development of alternative metabolic pathways in bacteria is a complex process that involves multiple genetic changes, making it a less common but potentially more concerning form of resistance than single-gene resistance mechanisms. For example, when sulfonamides block the production of folate by inhibiting dihydropteroate synthase, resistant bacteria can develop alternative pathways to acquire or synthesize folate through different enzymes or uptake mechanisms. Similarly, bacteria may develop resistance to glycopeptide antibiotics like vancomycin by altering cell wall precursors from D-Ala-D-Ala to D-Ala-D-Lac, which prevents vancomycin binding.
Examples of Alternative Metabolic Pathways
- Methicillin-resistant Staphylococcus aureus (MRSA) produces an alternative penicillin-binding protein (PBP2a) that continues cell wall synthesis when normal PBPs are inhibited by beta-lactams 1.
- Acinetobacter species have developed resistance to carbapenems due to the production of IMP-type metalloenzymes or carbapenemases of the OXA type 1.
- Stenotrophomonas maltophilia is uniformly resistant to carbapenems due to a ubiquitous metallo-β-lactamase 1.
Importance of Understanding Alternative Metabolic Pathways
Understanding these alternative metabolic pathways is crucial for developing new antimicrobials that can overcome resistance by targeting multiple pathways simultaneously or by inhibiting the alternative routes themselves. This is particularly important in the context of increasing antimicrobial resistance, where the development of new antimicrobials is critical to ensuring effective treatment of infections. The most recent evidence suggests that a comprehensive approach to addressing AMR, including the development of new antimicrobials and the optimization of existing treatment strategies, is necessary to mitigate the impact of alternative metabolic pathways on patient outcomes 1.
From the FDA Drug Label
The FDA drug label does not answer the question.
From the Research
AMR Mechanism - Alternative Metabolic Pathways
- The development of antimicrobial resistance (AMR) is a major public health threat, and alternative approaches are being explored to overcome it 2.
- One of the mechanisms of AMR is the evolution of alternative metabolic pathways that allow bacteria to survive and thrive in the presence of antimicrobials.
- Research has shown that combination therapies, bacteriophage therapy, antimicrobial adjuvants therapy, and the application of nanotechnology may be effective in enhancing the efficacy of existing antimicrobials 2, 3.
- Immunotherapy and CRISPR/Cas technology are also being explored as novel strategies to combat AMR 3.
- The use of β-lactam/β-lactamase inhibitors, such as ceftazidime/avibactam, meropenem/vaborbactam, and imipenem/relebactam, has shown promise in treating multidrug-resistant infections 4, 5, 6.
- However, resistance to these novel molecules has been reported, and the mechanisms of resistance include porin deficiencies, increasing carbapenemase expression, and/or enzyme mutations 6.
Alternative Metabolic Pathways and AMR
- The emergence of AMR is often driven by the ability of bacteria to adapt and evolve alternative metabolic pathways that allow them to survive and thrive in the presence of antimicrobials.
- Understanding these alternative metabolic pathways is crucial in developing effective strategies to combat AMR.
- Research has shown that the use of combination therapies and novel antimicrobial agents can help to overcome AMR by targeting multiple pathways and mechanisms simultaneously 2, 3.
- The development of new antimicrobial agents and the use of alternative approaches, such as bacteriophage therapy and immunotherapy, may also help to combat AMR by targeting alternative metabolic pathways 3, 4.