Late-Stage Modification of Aminoglycoside Antibiotics Overcomes Bacterial Resistance Mediated by APH(3') Kinases

Area of Science:

• Medicinal Chemistry
• Antimicrobial Resistance
• Organic Synthesis

Background:

• Antimicrobial resistance, particularly to last-resort aminoglycoside antibiotics, is a growing global health threat.
• A key resistance mechanism involves bacterial O-phosphotransferases [APH(3´)s] that phosphorylate aminoglycosides at the 3´-position.
• Existing methods for modifying aminoglycosides to overcome this resistance are complex and not industrially viable.

Purpose of the Study:

• To develop a novel, efficient synthetic strategy for modifying aminoglycosides at the 3´-position.
• To create new aminoglycoside derivatives that circumvent APH(3´)-mediated resistance.
• To provide a method attractive to the pharmaceutical industry for developing new antibiotics.

Main Methods:

• Development of a regioselective modification of aminoglycosides via palladium-catalyzed oxidation at the 3´-position.
• Synthesis of novel aminoglycoside antibiotic candidates using the developed method.
• Evaluation of the synthesized candidates for their efficacy against APH(3´)-mediated resistance.

Main Results:

• A novel and efficient palladium-catalyzed oxidation method for regioselective modification of aminoglycosides was established.
• Two novel aminoglycoside antibiotic candidates were successfully synthesized in only four steps.
• These candidates demonstrated effectiveness in overcoming APH(3´)-mediated antimicrobial resistance.

Conclusions:

• The developed palladium-catalyzed oxidation offers a practical approach for structural modification of aminoglycosides.
• This method facilitates the creation of new antibiotic candidates capable of overcoming significant resistance mechanisms.
• The strategy presents a viable route for combating multidrug-resistant bacterial infections and addressing the limitations of current antibiotic development.