Antibiotic Combination Therapy: A Strategy to Overcome Bacterial Resistance to Aminoglycoside Antibiotics

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.

Membrane-Active Cyclic Amphiphilic Peptides: Broad-Spectrum Antibacterial Activity Alone and in Combination with Antibiotics

“…The spread and danger of multidrug-resistant infection force the medical community to rely on additional broad-spectrum antibiotics to cure these infections, leading to more resistance . This has become a concerning issue because of the limited options of antimicrobial agents currently available to fight against these pathogens. − The lack of effective antibiotic options in the market is because of slow pace, high cost, and low selling prices of new antibiotics . Combination therapy can deal with and overcome antimicrobial resistance and repurpose existing antibiotics .…”

In Vitro Assessment of the Combination of Antibiotics against Some Integron-Harbouring Enterobacteriaceae from Environmental Sources

“…Although they have been used for several decades to treat infections caused by non-fastidious Gram-negative bacteria [ 30 ], the most prevalent bacterial resistance mechanisms in this antibiotic class are the enzymatic modification aminoglycoside antibiotics [ 31 ]. The enzymes belong to families, such as aminoglycoside phosphotransferases (APHs), aminoglycoside acetyltransferases (AACs), and aminoglycoside adenyl transferases (ANTs) [ 32 , 33 ]. These enzymes are often encoded on gene cassettes of integrons, also present in the isolates investigated in this study.…”

“…Here, K. pneumoniae (KP1) was resistant against ceftazidime, while gentamicin showed better activity but was not bactericidal against the isolate. It has been reported that β-lactams, such as ceftazidime, are known to break the bacterial cell wall in a non-fatal way, allowing aminoglycosides, such as gentamicin, to enter bacteria and increase their killing effectiveness [ 33 , 34 ]. In another study, aminoglycosides, due to their synergistic antibacterial properties, were combined with β-lactam antibiotics, which broadened the scope of treatment, accelerated bacterial clearance and enhanced antibiotic resistance [ 35 ].…”

“…In another study, aminoglycosides, due to their synergistic antibacterial properties, were combined with β-lactam antibiotics, which broadened the scope of treatment, accelerated bacterial clearance and enhanced antibiotic resistance [ 35 ]. Several other studies have reported the combination of aminoglycosides with β-lactams for treating MDR bacteria species [ 33 , 36 , 37 ].…”

Artemisinin derivative DHA27 enhances the antibacterial effect of aminoglycosides against Pseudomonas aeruginosa by inhibiting mRNA expression of aminoglycoside-modifying enzymes

“…Acquired 16S rRNA methyltransferase (16S-Rmtase) is one of the main mechanisms of aminoglycoside antibiotic resistance in bacteria. The enzyme uses S-adenosine methionine (SAM) as a cofactor to add methyl groups to specific residues of 16S rRNA ( Wang et al, 2022 ). AGs have a lower affinity for methylated 16S rRNA than for non-methylated 16S rRNA, which makes the bacteria resistant to a broad spectrum of AGs ( Wachino et al, 2020 ).…”