Nature, a rich source of bioactive natural products, serves as a massive pool of drug candidates for the pharmaceutical industry. However, the supply of these structurally complex chemicals is costly as most of the natural products are scarce in nature, thus requiring de novo synthesis. The supply chain issue hinders the development of novel therapeutic agents from natural products. Microbial synthesis, based on the expression of biosynthetic genes in a suitable microbial host to produce certain chemicals, is a sustainable strategy to produce complex natural products. However, this strategy requires gaining insights into the biosynthesis of target molecules. Most natural products are biosynthetically unknown or not fully elucidated; thus, the sole application of microbial synthesis strategy to produce a given molecule is challenging. In this review, we highlight a strategy that combines microbial and chemical syntheses to tackle the supply chain issue in developing drugs from natural products. We believe this strategy can revive the drug development pipeline for natural products.
Biological Products/chemistry* ; Aminoglycosides

BACKGROUND: High-level gentamicin and streptomycin disks are not easily available, despite their critical role in detection of high-level resistance to aminoglycosides in enterococci. Therefore, the possibility of applicating home-made disks to test high-level resistance of enterococci to aminoglycosides was evaluated. METHODS: The disk diffusion method using home-made disks was compared with minimal inhibitory concentrations(MIC) in 53 clinical isolates of enterococci, and, the stability of the disks were also evaluated by disk diffusion testing, biweekly, for 14 weeks. RESULTS: The high-level resistance rates to gentamicin(GM) and streptomycin(SM) were 60% and 43%, respectively. Thirty eight % of the enterococci were highly resistant in both GM and SM. The results of the disk diffusion method were consistent with the MIC until 10 weeks after production of the disks. After 12 weeks, the inhibition zones of GM- or SM-susceptible strains decreased by 2.9-3.9 mm, and the discrepancy rates were 5-24% between the results of the MIC and disk diffusion method. The storage temperature of -20degrees C versus -70degrees C showed no difference in the inhibition zone. CONCLUSION: It has been demonstrated that home-made high-level GM and SM disks are stable at -20degrees C for 10 weeks, and the results of disk diffusion method on the disks show they are applicable for the test of susceptibility of aminoglycosides to enterococci.
Aminoglycosides ; Diffusion ; Enterococcus ; Gentamicins ; Streptomycin

Since the characteristics of aminoglycoside ototoxicity is typically bilaterally symmetric progression of cochlea-vestibular dysfunction, a unilateral involvement has rarely been reported. However, ototoxicity can be asymmetric or focal after systemic aminoglycoside treatment. The authors report 2 cases of asymmetric or focal audiovestibular deficits in patients treated with systemic aminoglycoside. In such cases, further investigations are also necessary to rule out other possible causes of unilateral sensorineural hearing loss such as cerebellopontine angle tumors.
Aminoglycosides ; Hearing Loss, Sensorineural ; Humans ; Neuroma, Acoustic

As an important aminoglycosides antibiotic, gentamicin has been used clinically over decades. With the development in modern biological technology, the mechanisms of gentamicin action and resistance, its biosynthesis and structural modification were studied in great depth. Meanwhile, its emerging novel bioactivities and potential applications are also under extensive exploration. Here we summarize the latest progresses and prospects towards the future development of gentamicin for more efficient and effective uses.
Aminoglycosides ; biosynthesis ; chemistry ; Gentamicins ; biosynthesis ; chemistry

We analysed retrospectively pharmacokinetic parameters of gentamicin and amikacin in 44 and 58 Korean pediatric patients, respectively, with normal renal function. Pharmacokinetic parameters were calculated from two concentrations in serum by method of Sawchuck. There was wide individual variation in peak serum concentrations of gentamicin and amikacin, Administration of the usually recommended doses yielded subtherapeutic concentrations in 47% and 82%, respectevely, of patients in the peak concentrations of gentamicin and amikacin. The volumes of distribution of gentamicin and amikacin in children of over 1 year of age were 0.37+/-0.13L/kg and 0.41+/-0.13L/kg which are greater than those reported from the western countries. We conclude that the wide individual variation and high frequency of subtherapeutic levels in the peak concentrations of gentamicin and amikacin obtained by usually recommended dosage as well as the narrow safety margin of these drugs necessitate monitoring of serum concentration and adjustment of individual dosage regimen early in the course of treatment with aminoglycosides.
Amikacin* ; Aminoglycosides ; Child* ; Gentamicins* ; Humans ; Pharmacokinetics* ; Retrospective Studies

Aminoglycosides are one of the clinically relevant antibiotics. They kill bacteria by binding to bacterial 30S subunit of ribosome. Resistance to aminoglycosides occurs by three different mechanisms: 1. Production of an enzyme that modifies aminoglycosides, 2. Impaired entry of aminoglycoside into the cell by altering the OMP permeability, decreasing inner membrane transport, or active efflux, 3. The receptor protein on the 30S ribosomal subunit may be deleted or altered as a result of a mutation. By far, enzymatic modification has been the most important mechanism. In this review, the mechanisms of action and resistance, and the prevalence of resistance due to acquisition of enzymes are briefly described.
Aminoglycosides ; Anti-Bacterial Agents ; Bacteria ; Membranes ; Permeability ; Prevalence ; Ribosome Subunits ; Ribosomes

Aminoglycosides are frequently used antibiotics in children. The multiple daily dosing (MDD) in infants and children is twice or three times daily depending on age. Recent studies in adults have shown that once daily dosing (ODD) maximizes the bactericidal activity and might minimize the toxicity of antibiotics. So, I reviewed many studies about efficacy, toxicity and cost effectiveness of ODD of aminoglycosides in children. Most studies suggest that ODD compared with MDD of aminoglycosides is theoretically more efficacious and has no higher toxicity in infants and children. But, the total number of patients included in the studies is not large. Multi-center, controlled prospective studies are required in larger numbers of infants and children to determine the efficacy and safety of the ODD regimen in children before ODD of aminoglycosides can be recommended for routine use.
Adult ; Aminoglycosides ; Anti-Bacterial Agents ; Child ; Cost-Benefit Analysis ; Humans ; Infant

Multidrug-resistant tuberculosis(MDR-TB), resistant to at least the two main TB drugsisoniazid and rifampicin, has been a threat to TB control because the treatment requires more toxic drugs and longer period with poor treatment outcomes. Recently, more serious concerns have been raised about extensively drug resistant-tuberculosis (XDR-TB), which shows resistance to fluoroquinolones and aminoglycosides in addition to isoniazid and rifampicin. XDR-TB is a serious global health threat because the cure is very difficult as few sensitive anti-TB drugs remain. XDR-TB develops when first-and second-line anti-TB drugs are misused during the course of treatment, most commonly due to poor compliance of the patients to the treatment regimen. People with XDR-TB can pass the XDR-TB bacteria to other people. Thus, every effort should be made to prevent the development of XDR-TB by establishing an effective TB control program maximizing patient adherence to prescribed anti-TB regimen and minimizing contact of XDR-TB patients with other people to prevent the spread of XDR-TB.
Aminoglycosides ; Bacteria ; Compliance ; Extensively Drug-Resistant Tuberculosis ; Fluoroquinolones ; Humans ; Isoniazid ; Patient Compliance ; Rifampin ; Tuberculosis

Antimicrobials are one of the most widely prescribed classes of therapeutic agents. Although adverse effects of antimicrobials are generally minimal and reversible, serious sequelae can sometimes remain, such as unusual forms of renal failure, acid base disturbance and electrolyte abnormalities. Many antimicrobials, especially vancomycin or aminoglycosides, are associated with development of acute renal failure caused by acute tubular necrosis, allergic acute interstitial nephritis, or vasculitis. Besides, some antimicrobial agents can cause serious fluid and electrolyte imbalance. To prevent these serious consequences, early recognition and correction of their harmful renal and electrolyte effects are required.
Acute Kidney Injury ; Aminoglycosides ; Anti-Infective Agents ; Necrosis ; Nephritis, Interstitial ; Renal Insufficiency ; Vancomycin ; Vasculitis

In order to study the effects of aminoglycosides on leukochemotaxis in rats, the degree of leukocyte infiltration and differential leukocyte count were observed at the experimentally inflamed tissue by incision of the skin and the application of endotoxin subcutaneously after the administration of gentamicin and streptomycin respectively. The results obtained were as follows. 1) In the control group treated with physiological, saline, the infiltration of leukocytes was relatively scant in the first nne hour, conspicuously increased three hours later, and persisted for 24 hours. 2) In the gentamicin and streptomycin treated groups, infiltration of leukocytes was srnall in number in the first hour. There after it gradually increased over a period of time. However it was a little less in the gentamicin and streptomycin injected group compared with the control. 3)In the control group, about 90% of the infiltrated cells was neutrophils up to three hours. However 24 hours later, the neutrophils reached about 40%. On the other hand, monocytes and lymphocytes were 4% in the first hour, and after 24 hours the monocytes was 19 to 24% and lymphocytes were 31 to 36%. 4) In the gentamicin and streptomycin injected grougs, about 90% of the infiltrated cells was neutrophils for the first three hours. The numbers gradually decreased to 56-66% and 51~54% after 24 hours, respectively. The percentage of both monocytes and lymphocytes was 2~4% after ome hour, and increased to 15~29 and 17~29% after 24 houre, respectively.
Aminoglycosides* ; Animals ; Gentamicins ; Hand ; Leukocyte Count ; Leukocytes ; Lymphocytes ; Monocytes ; Neutrophils ; Rats* ; Skin ; Streptomycin