Tobramycin Variants with Enhanced Ribosome-Targeting Activity

Area of Science:

• Microbiology
• Medicinal Chemistry
• Molecular Biology

Background:

• Aminoglycoside (AG) resistance in bacteria is a growing global health concern.
• Existing AGs face limitations due to resistance mechanisms and suboptimal ribosome targeting.
• There is a critical need for novel AGs with improved efficacy and resistance evasion.

Purpose of the Study:

• To synthesize and evaluate novel tobramycin (TOB) derivatives for enhanced antimicrobial activity.
• To investigate the ability of these derivatives to overcome bacterial resistance mechanisms.
• To determine if modified TOB compounds exhibit improved ribosome-targeting efficiency.

Main Methods:

• Chemical derivatization of tobramycin (TOB) by introducing 37 distinct thioether groups at the 6''-position.
• Assessment of synthesized compounds as substrates for tobramycin-modifying enzymes (AMEs).
• In vitro evaluation of antibacterial activity and ribosome-targeting specificity of the derivatives.

Main Results:

• Most synthesized thioether derivatives were poorer substrates for TOB-targeting AMEs.
• Thirteen derivatives demonstrated superior antibacterial activity compared to the parent TOB.
• These thirteen compounds maintained their specific ribosome-targeting capability.
• In vitro analyses elucidated the mechanism of action, identifying three compounds with significantly enhanced ribosome-targeting activity.

Conclusions:

• Chemical modification of tobramycin can yield derivatives with potent antibacterial activity against resistant strains.
• The novel derivatives exhibit reduced susceptibility to common aminoglycoside-modifying enzymes.
• Specific modifications enhance ribosome targeting, offering a promising strategy for developing new antibiotics.