Abstract
After the first aminoglycoside antibiotic streptomycin being applied in clinical practice in the mid-1940s, aminoglycoside antibiotics (AGAs) are widely used to treat clinical bacterial infections and bacterial resistance to AGAs is increasing. The bacterial resistance to AGAs is owed to aminoglycoside modifying enzyme modification, active efflux pump gene overexpression and 16S rRNA ribosomal subunit methylation, leading to modification of AGAs’ structures and decreased concentration of drugs within bacteria. As AGAs’s side effects and bacterial resistance, the development of AGAs is time-consuming and difficult. Because bacterial resistance may occur in a short time after application in clinical practice, it was found that the antibacterial effect of the combination was not only better than that of AGAs alone but also reduce the dosage of antibiotics, thereby reducing the occurrence of side effects. This article reviews the clinical use of AGAs, the antibacterial mechanisms, the molecular mechanisms of bacterial resistance, and especially focuses a recent development of the combination of AGAs with other drugs to exert a synergistic antibacterial effect to provide a new strategy to overcome bacterial resistance to AGAs.
Highlights
Streptomycin was the first discovered aminoglycoside antibiotic (AGA) to be used for tuberculosis treatment in the mid-1940s (Schatz et al, 2005)
New Center for Disease Control (CDC) data show that despite the growing threat of antibiotic resistance in the United States, for example, erythromycin-resistant invasive group A streptococcus increased by 351%, drug-resistant neisseria gonorrhoeae increased by 124%, and ESBL-producing enterobacteriaceae increased by 50%, the number of deaths has decreased since the 2013 report, including an 18% reduction in overall deaths and a 28% reduction in hospital deaths resulting from antibiotic resistance (Antibiotic resistance threats in the United States, 2019, 2019)
In the study of the synergistic antibacterial effect of antimicrobial peptide PMAP-36 or PRW4 combined with gentamicin against E. coli and S. aureus, it was found that adenosine monophosphate (AMP) and gentamicin had a synergistic (fractional lethal concentration (FLC) < 0.5) and a partial synergistic effect
Summary
Streptomycin was the first discovered aminoglycoside antibiotic (AGA) to be used for tuberculosis treatment in the mid-1940s (Schatz et al, 2005). The structural feature of 4,5 disubstituted 2-DOS AGAs is that the hydroxyl groups at the C-4 and C-5 positions of the 2-DOS ring are substituted and connected to the sugar ring by a glycosidic bond; in. 4,6-disubstituted 2-DOS AGAs, the hydroxyl groups at the C-4 and C-6 positions of the 2-DOS ring are substituted and connected to the sugar ring by a glycosidic bond These sugar units generally have multiple hydroxyl and amino groups, so they have the advantages of good water solubility, good functionality and wide antibacterial spectrum (Johnston et al, 2002). AGAs development can be divided into three stages, known as three generations, based on chemical structure, antibacterial spectrum and resistance to bacterial modification enzymes (Lin, 2001). Among non-fermentative gram-negative bacilli, P. aeruginosa was mostly sensitive to gentamicin and amikacin, while acinetobacter was severely resistant to the two AGAs (Hu et al, 2021) (Table 2)
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