Gentamicin

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. Special populations Pregnancy and breastfeeding 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. ==Contraindications==

Gentamicin should not be used if a person has a history of hypersensitivity, such as anaphylaxis, or other serious toxic reaction to gentamicin or any other aminoglycosides. ==Adverse effects==

Adverse effects of gentamicin can range from less severe reactions, such as nausea and vomiting, to more severe reactions including: Inner ear 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. Factors that increase the risk of inner ear damage include: • Increased age • High blood uric acid levels • Kidney dysfunction • Liver dysfunction • Higher doses • Long courses of therapy • Also taking strong diuretics (e.g., furosemide) ==Pharmacology==

Mechanism of action Gentamicin is a bactericidal antibiotic that works by binding the 30S subunit of the bacterial ribosome, negatively impacting protein synthesis. The primary mechanism of action is generally accepted to work through ablating the ability of the ribosome to discriminate on proper transfer RNA and messenger RNA interactions. 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. Moreover, it has been observed that gentamicin can cause a substantial slowdown in the overall elongation rate of peptide chains in live bacterial cells, independent of the misincorporation of amino acids. This finding indicates that gentamicin not only induces errors in protein synthesis but also broadly hampers the efficiency of the translation process itself. An additional 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, creating a pool of inactive ribosomes that can no longer re-initiate and translate new proteins. ==Chemistry==

Structure 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. Kanamycins and tobramycin exhibit similar structures. Sisomicin is 4,5-dehydrogentamicin-C1a. Components Gentamicin is composed of a number of related gentamicin components and fractions which have varying degrees of antimicrobial potency. 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. Biosynthesis 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. A range of pH from 6.8 to 7.5 is used for gentamicin biosynthesis and the aeration is determined by independent experimentation reliant on type of growth medium and species of Micromonospora. ==History==

Gentamicin is produced by the fermentation of Micromonospora purpurea. It was discovered in 1963 by Weinstein, Wagman et al. at Schering Corporation in Bloomfield, N.J. while working with source material (soil samples) provided by Rico Woyciesjes. ==Research==

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. == References ==