Restoring susceptibility to aminoglycosides: identifying small molecule inhibitors of enzymatic inactivation
Angel J Magaña1, Jan Sklenicka1, Clemencia Pinilla2
1Center for Applied Biotechnology Studies, Department of Biological Science, College of Natural Sciences and Mathematics, California State University Fullerton Fullerton CA 92831 USA mtolmasky@fullerton.edu.
Abstract:
Growing resistance to antimicrobial medicines is a critical health problem that must be urgently addressed. Adding to the increasing number of patients that succumb to infections, there are other consequences to the rise in resistance like the compromise of several medical procedures and dental work that are heavily dependent on infection prevention. Since their introduction in the clinics, aminoglycoside antibiotics have been a critical component of the armamentarium to treat infections. Still, the increase in resistance and their side effects led to a decline in their utilization. However, numerous current factors, like the urgent need for antimicrobials and their favorable properties, led to renewed interest in these drugs. While efforts to design new classes of aminoglycosides refractory to resistance mechanisms and with fewer toxic effects are starting to yield new promising molecules, extending the useful life of those already in use is essential. For this, numerous research projects are underway to counter resistance from different angles, like inhibition of expression or activity of resistance components. This review focuses on selected examples of one aspect of this quest, the design or identification of small molecule inhibitors of resistance caused by enzymatic modification of the aminoglycoside. These compounds could be developed as aminoglycoside adjuvants to overcome resistant infections.
Insights
Antimicrobial resistance is a major health threat. This review explores small molecules that inhibit enzymes causing aminoglycoside antibiotic resistance, potentially reviving these crucial drugs.
Area of Science:
- Microbiology
- Pharmacology
- Medicinal Chemistry
Background:
- Antimicrobial resistance (AMR) poses a critical global health threat, compromising medical procedures and increasing infection-related mortality.
- Aminoglycoside antibiotics, once vital, have seen reduced use due to resistance and side effects, despite renewed interest driven by urgent antimicrobial needs.
- Countering AMR requires innovative strategies, including developing new aminoglycosides and extending the utility of existing ones.
Purpose of the Study:
- To review small molecule inhibitors targeting enzymatic modification of aminoglycoside antibiotics.
- To highlight strategies for overcoming aminoglycoside resistance through inhibition of resistance-conferring enzymes.
- To explore the potential of these inhibitors as adjuvants to restore aminoglycoside efficacy.
Main Methods:
- Literature review focusing on small molecule inhibitors of aminoglycoside-modifying enzymes.
- Analysis of research on mechanisms of aminoglycoside resistance.
- Selection and discussion of representative examples of inhibitor compounds.
Main Results:
- Enzymatic modification is a key mechanism of aminoglycoside resistance.
- Small molecules capable of inhibiting these resistance enzymes have been identified and designed.
- These inhibitors show promise in restoring aminoglycoside activity against resistant bacteria.
Conclusions:
- Small molecule inhibitors of aminoglycoside-modifying enzymes represent a promising strategy to combat AMR.
- These compounds could serve as adjuvants, enhancing the effectiveness of existing aminoglycoside antibiotics.
- Further development of these inhibitors is crucial for extending the lifespan of essential antimicrobial therapies.
