Drug resistance backfires on bacteria
Aminoglycosides constitute broad-spectrum antibiotics commonly used against many bacterial infections and work by interfering with bacterial protein synthesis. However, years of clinical use have led to emergence of bacterial resistance to this family of drugs, thereby limiting their efficacy in the clinic. The mechanism behind this drug resistance involves the evolution of novel enzymes capable of modifying and inactivating aminoglycosides.There are no synthetic methodologies for the selective modification of one particular amine in an aminoglycoside compound. Scientists of the EU-funded AAC project followed an interesting approach for synthesising novel aminoglycoside-based antibiotics. In particular, they used several aminoglycoside-modifying enzymes that evolved in certain resistant bacterial strains to modify existing aminoglycoside-based drugs.Their approach yielded a series of novel analogues with antimicrobial activity in bacteria with resistance to traditional aminoglycoside antibiotics. This clearly indicates their ability to overcome several drug resistance pathways. The same method was exploited for the generation of antibiotics that target bacterial cell membranes. With special focus on the antibiotic tobramycin, researchers synthesised various aminoglycoside analogues capable of bacterial cell membrane disruption.Collectively the AAC work presented an interesting concept for overcoming evolutionary mechanisms in bacteria to produce next generation antibiotics. This novel chemoenzymatic approach opens up new avenues of drug synthesis capable of tackling drug-resistant strains.
Keywords
Aminoglycoside antibiotics, resistant bacteria, aminoglycoside-modifying enzymes
