Sisomicin, Netilmicin and Dibekacin

Abstract

Sisomicin is a naturally occurring aminoglycoside antibiotic produced by Micromonospora inyoensis, while dibekacin and netilmicin are both semisynthetic aminoglycosides. Dibekacin is 3',4'-dideoxykanamycin B and netilmicin is 1-N-ethyl sisomicin. In both cases, these modifications render the agents insusceptible to some of the enzymes found in resistant strains of bacteria which inactivate the parent compounds. Antibacterial activity: All 3 drugs show bactericidal activity against a wide range of Gram-negative bacteria (including E. coli, Enterobacter, Klebsiella and Proteus spp. and Ps. aeruginosa) and also against staphylococci; however, in common with other amino-glycosides, streptococci are usually resistant (except when beta-lactam antibiotics are used in combination) and anaerobic organisms are not sensitive. Sisomicin is closely related structurally to gentamicin Cla, but in vitro studies have shown it to have superior activity to gentamicin against Ps. aeruginosa, closely paralleling the activity of tobramycin, while still possessing the high activity of gentamicin against Serratia and other Gram-negative rods. However, sisomicin is inactivated by virtually all bacterial enzymes which inactivate gentamicin and tobramycin. Nevertheless, it retains useful activity against a number of gentamicin-resistant strains of Ps. aeruginosa which are resistant by non-enzymatic (possibly permeability barrier) mechanisms; in this respect it closely resembles tobramycin. Dibekacin closely resembles tobramycin structurally and in vitro it seems to have a very similar antibacterial spectrum, including activity against some strains of Ps. aeruginosa resistant to gentamicin. Netilmicin has a generally broader antibacterial spectrum than gentamicin, tobramycin, sisomicin or debekacin and is resistant to inactivation by phosphorylating and adenylylating enzymes; however, it is inactivated by all acetylases, apart from acetylase 3-I. Its spectrum is therefore not as wide as that of amikacin against 'gentamicin-resistant' strains. Nonetheless, it is intrinsically more active than amikacin, weight-for-weight, against sensitive strains, apart possibly from Ps. aeruginosa. In fact, its activity against species of the Enterobacteriaceae and staphylococci sensitive to gentamicin is of the same order as the latter and possibly better for Klebsiella-Enterobacter species. All 3 agents show marked antibacterial synergy with a variety of beta-lactam antibiotics against a range of bacteria. Pharmacokinetically, sisomicin, netilmicin and dibekacin all behave like gentamicin. All 3 drugs are excreted in the urine unchanged and have beta-phase elimination half-lives of around 2 to

l-Pentoses in Biological and Medicinal Applications

“…Netilmicin was found to have potency similar to gentamicin against aminoglycoside-susceptible gram-negative bacteria in both in vitro and in vivo tests . Regardless of the marginal improvements in terms of antibacterial activity, clinical studies have demonstrated that netilmicin is significantly less nephrotoxic than gentamicin . Similar to other aminoglycoside antibiotics, netilmicin exhibits in vitro synergistic effects against a wide range of organisms in combination with other antibacterial drugs.…”

Draft Genome Sequence of Micromonospora sp. Strain WMMA1996, a Marine Sponge-Associated Bacterium

“…Members of the genus Micromonospora are important producers of antibiotics, having yielded more than 700 compounds of medical value over the years ( 1 ). Compounds such as the aminoglycoside antibiotics gentamicin ( 2 , 3 ) and netilmicin ( 2 ), the antitumor antibiotics lomaiviticins ( 4 – 7 ) and tetrocarcins ( 8 , 9 ), the anthracycline antibiotics ( 10 – 12 ), and the enediyne calicheamicin ( 13 – 15 ) highlight both the structural diversity and medicinal impact of Micromonospora -derived natural products. In addition to compounds with clear antimicrobial or anticancer activities, members of the Micromonospora have produced natural products such as juvenimicin C ( 16 ), an activator of phase II detoxifying enzymes with cancer chemopreventive activities, and diazepinomicin, a farnesylated dibenzodiazepine with antioxidant and antiproteolytic activities proposed to protect against an assortment of age-related diseases such as diabetes, atherosclerosis, and various cancers ( 17 ).…”

Structural and phylogenetic analyses of resistance to next-generation aminoglycosides conferred by AAC(2′) enzymes

“…Plazomicin, the latest next-generation aminoglycoside, was approved for clinical use by the U.S. Food and Drug Administration in 2018 and is the second semisynthetic derivative of sisomicin 10 , 13 . The first, netilmicin, incorporated an ethyl group at the N1 position.…”