Гентамицин: антибиотик, применение и побочные эффекты

Antibiotic medication

Gentamicin is an aminoglycoside antibiotic used to treat several types of bacterial infections. This may include bone infections, endocarditis, pelvic inflammatory disease, meningitis, pneumonia, urinary tract infections, and sepsis among others. It is often only used for two days until bacterial cultures determine what specific antibiotics the infection is sensitive to. The dose required should be monitored by blood testing. Gentamicin is a type of aminoglycoside The antibiotic is collected from the culture of the Micromonospora by perforating the cell wall of the bacterium. Current research is underway to understand the biosynthesis of this antibiotic in an attempt to increase expression and force secretion of gentamicin for higher titer. Gentamicin is on the World Health Organization's List of Essential Medicines. The World Health Organization classifies gentamicin as critically important for human medicine. It is available as a generic medication.

Gentamicin is active against a wide range of bacterial infections, mostly Gram negative bacteria including Pseudomonas, Proteus, Escherichia coli, Klebsiella pneumoniae, Enterobacter aerogenes, Serratia, and the Gram positive Staphylococcus. Gentamicin is used in the treatment of respiratory tract infections, urinary tract infections, blood, bone and soft tissue infections of these susceptible bacteria. There is insufficient evidence to support gentamicin as the first line treatment of Neisseria gonorrhoeae infection. Gentamicin is not used for Neisseria meningitidis or Legionella pneumophila bacterial infections (because of the risk of the person going into shock from lipid A endotoxin found in certain Gram negative organisms). Gentamicin is also useful against Yersinia pestis (responsible for plague), its relatives, and Francisella tularensis (the organism responsible for tularemia often seen in hunters and trappers). Some Enterobacteriaceae, Pseudomonas spp., Enterococcus spp., Staphylococcus aureus and other Staphylococcus spp. have varying degrees of resistance to gentamicin.

Gentamicin is not recommended in pregnancy unless the benefits outweigh the risks for the mother. Gentamicin can cross the placenta and several reports of irreversible bilateral congenital deafness in children have been seen. Intramuscular injection of gentamicin in mothers can cause muscle weakness in the newborn. Kidney function should be checked periodically during therapy. Long term effects of treatment can include hearing loss and balance problems. Hypocalcemia, hypokalemia, and muscle weakness have been reported when used by injection.

About 11% of the population who receives aminoglycosides experience damage to their inner ear. The common symptoms of inner ear damage include tinnitus, hearing loss, vertigo, trouble with coordination, and dizziness. To reduce the risk of ototoxicity during treatment, it is recommended to stay hydrated. Typically, if an incorrect tRNA pairs with an mRNA codon at the aminoacyl site of the ribosome, adenosines 1492 and 1493 are excluded from the interaction and retract, signaling the ribosome to reject the aminoacylated tRNA::Elongation Factor Thermo Unstable complex. However, when gentamicin binds at helix 44 of the 16S rRNA, it forces the adenosines to maintain the position they take when there is a correct, or cognate, match between aa tRNA and mRNA. This leads to the acceptance of incorrect aa tRNAs, causing the ribosome to synthesize proteins with wrong amino acids placed throughout (roughly every 1 in 500). The non functional, mistranslated proteins misfold and aggregate, eventually leading to death of the bacterium. A secondary mechanism has been proposed based on crystal structures of gentamicin in a secondary binding site at helix 69 of the 23S rRNA, which interacts with helix 44 and proteins that recognize stop codons. At this secondary site, gentamicin is believed to preclude interactions of the ribosome with ribosome recycling factors, causing the two subunits of the ribosome to stay complexed even after translation completes. This creates a pool of inactive ribosomes that can no longer re initiate and translate new proteins.

Since gentamicin is derived from the species Micromonospora, the backbone for this antibiotic is the aminocyclitol 2 deoxystreptamine. This six carbon ring is substituted at the carbon positions 4 and 6 by the amino sugar molecules cyclic purpurosamine and garosamine, respectively. The R1 and R2 can have the follow substitutions for some of the species in the gentamicin complex. The main components of gentamicin include members of the gentamicin C complex: gentamicin C1, gentamicin C1a, and gentamicin C2 which compose approximately 80% of gentamicin and have been found to have the highest antibacterial activity. Gentamicin A, B, X, and a few others make up the remaining 20% of gentamicin and have lower antibiotic activity than the gentamicin C complex.

The complete biosynthesis of gentamicin is not entirely elucidated. The genes controlling the biosynthesis of gentamicin are of particular interest due to the difficulty in obtaining the antibiotic after production. Since gentamicin is collected at the cell surface and the cell surface must be perforated somehow to obtain the antibiotic. When X2 is acted on by the cobalamin dependent radical S adenosyl L methionine enzyme GenK, the carbon position 6' is methylated to form the pharmacologically active intermediate G418 G418 then undergoes dehydrogenation and amination at the C6' position by the dehydrogenase gene, GenQ, to generate the pharmacologically active JI 20B, although another intermediate, 6' dehydro 6'oxo G418 (6'DOG) is proposed to be in between this step and for which the gene GenB1 is proposed as the aminating gene. JI 20B is dehydroxylated and epimerized to first component of the gentamicin C complex, gentamicin C2a which then undergoes an epimerization by GenB2 and then a N methylation by an unconfirmed gene to form the final product in this branch point, gentamicin C1. C1a then undergoes an N methylation by an unconfirmed enzyme to form the final component, gentamicin C2b. Traditional fermentation used yeast beef broth, Phosphate ions, metal ions (cobalt and a few others at low concentration), various vitamins (mostly B vitamins), purine and pyrimidine bases are also supplemented into the growth medium to increase gentamicin production, but the margin of increase is dependent on the species of Micromonospora and the other components in the growth medium. With all of these aforementioned additives, pH and aeration are key determining factors for the amount of gentamicin produced.

Gentamicin is also used in molecular biology research as an antibacterial agent in tissue and cell culture, to prevent contamination of sterile cultures. Gentamicin is one of the few heat stable antibiotics that remain active even after autoclaving, which makes it particularly useful in the preparation of some microbiological growth media.