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[Biochemical and genetic mechanisms for bacteria to acquire aminoglycoside antibiotic resistance]
1National Institute of Health.
Abstract:
Aminoglycoside (AG)-modifying enzymes are the major biochemical basis for the AG resistance of clinically-occurring bacteria. Recent AG resistance profiles can be characterized by the involvement of AAC(6') in combination with other modifying enzymes in Gram negative bacteria. AAC(6')/APH(2") in Staphylococcus aureus is also remarkable. Genetic basis for the emergence or alteration of AG resistance profiles includes point mutations in the regulatory region or specific sites of the coding region of AG-modifying enzyme genes, and rearrangement of the genes caused by transposon and/or integron. In addition, semisynthetic AG antibiotics such as amikacin, arbekacin (ABK) and isepamicin were also reviewed for their stability to AG-modifying enzymes. ABK that has been widely used as an anti-MRSA drug in Japan is distinct from the other AGs because its monoacetylated derivatives (3"-N-acetylABK and 2'-N-acetylABK) by AG acetyltransferases, AAC(3) and AAC(2'), respectively, retain clear antibiotic activities. Based on this novel aspect and the lack of modification sites for APH(3') and ANT(4'), ABK should be regarded as the most refractory AG for bacteria to acquire resistance.
Insights
Aminoglycoside resistance in bacteria is often due to modifying enzymes. Arbekacin (ABK) shows superior stability against these enzymes, making it a promising antibiotic against resistant bacteria.
Area of Science:
- Microbiology
- Biochemistry
- Pharmacology
Context:
- Aminoglycoside (AG) resistance is a significant challenge in treating bacterial infections.
- Bacterial resistance often stems from aminoglycoside-modifying enzymes (AMEs).
- Emergence of resistance involves genetic alterations like mutations and gene rearrangements.
Purpose:
- To review the biochemical and genetic basis of aminoglycoside resistance.
- To evaluate the stability of semisynthetic aminoglycosides, including arbekacin (ABK), against AMEs.
- To highlight arbekacin's unique properties and potential as a potent antimicrobial agent.
Summary:
- Aminoglycoside resistance is primarily mediated by enzymes like AAC(6") and AAC(6")/APH(2").
- Genetic factors such as point mutations and transposon-mediated rearrangements contribute to resistance.
- Arbekacin (ABK) exhibits unique stability against AMEs, as its acetylated derivatives retain antibiotic activity, and it lacks modification sites for certain enzymes.
Impact:
- Arbekacin (ABK) demonstrates significant potential as a highly refractory aminoglycoside, challenging bacterial resistance mechanisms.
- Understanding AME profiles is crucial for developing effective strategies against multidrug-resistant bacteria.
- The distinct properties of ABK offer a novel therapeutic avenue, particularly against Methicillin-resistant Staphylococcus aureus (MRSA).