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ABSTRACT: Biosynthetically inspired manipulation of the antibiotic paromomycin led, in six high-yielding steps, to a ring A harboring an α,β-unsaturated 6'-aldehyde and an allylic 3'-methylcarbonate group. Tsuji deoxygenation in the presence of 5 mol % Pd(2)(dba)(3) and Bu(3)P granted access to a novel series of 3',4'-dideoxy-4',5'-dehydro ring A hybrids. The neomycin-sisomicin hybrid exhibited superior in vitro antibacterial activity to the parent compound neomycin.
Organic Letters 11/2011; 13(24):6476-9. · 5.86 Impact Factor
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Stephen Hanessian,
Alexandre Giguère,
Justyna Grzyb,
Juan Pablo Maianti,
Oscar M. Saavedra,
James B. Aggen,
Martin S. Linsell,
Adam A. Goldblum,
Darin J. Hildebrandt,
Timothy R. Kane,
Paola Dozzo,
Micah J. Gliedt,
Rowena D. Matias, Lee Ann Feeney,
Eliana S. Armstrong
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ABSTRACT: Deoxygenation of the diol groups in rings A and D of neomycin in combination with the introduction of an N1-(l)-HABA group in the 2-deoxystreptamine subunit (ring B) leads to a novel and potent antibiotic (1) with activity against strains of S. aureus carrying known aminoglycoside resistance determinants, as well as against an extended panel of Methicillin-resistant S. aureus isolates (n = 50). Antibiotic 1 displayed >64 fold improvement in MIC50 and MIC90 against this MRSA collection when compared to the clinically relevant aminoglycosides amikacin and gentamicin. The synthesis was achieved in six steps and 15% overall yield.Keywords: Aminoglycoside; antibiotics; deoxygenation; MRSA; enzymatic modification; resistance; neomycin analogues
09/2011;
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James B Aggen,
Eliana S Armstrong,
Adam A Goldblum,
Paola Dozzo,
Martin S Linsell,
Micah J Gliedt,
Darin J Hildebrandt, Lee Ann Feeney,
Aya Kubo,
Rowena D Matias,
Sara Lopez,
Marcela Gomez,
Kenneth B Wlasichuk,
Raymond Diokno,
George H Miller,
Heinz E Moser
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ABSTRACT: ACHN-490 is a neoglycoside, or "next-generation" aminoglycoside (AG), that has been identified as a potentially useful agent to combat drug-resistant bacteria emerging in hospitals and health care facilities around the world. A focused medicinal chemistry campaign produced a collection of over 400 sisomicin analogs from which ACHN-490 was selected. We tested ACHN-490 against two panels of Gram-negative and Gram-positive pathogens, many of which harbored AG resistance mechanisms. Unlike legacy AGs, ACHN-490 was active against strains expressing known AG-modifying enzymes, including the three most common such enzymes found in Enterobacteriaceae. ACHN-490 inhibited the growth of AG-resistant Enterobacteriaceae (MIC(90), ≤4 μg/ml), with the exception of Proteus mirabilis and indole-positive Proteae (MIC(90), 8 μg/ml and 16 μg/ml, respectively). ACHN-490 was more active alone in vitro against Pseudomonas aeruginosa and Acinetobacter baumannii isolates with AG-modifying enzymes than against those with altered permeability/efflux. The MIC(90) of ACHN-490 against AG-resistant staphylococci was 2 μg/ml. Due to its promising in vitro and in vivo profiles, ACHN-490 has been advanced into clinical development as a new antibacterial agent.
Antimicrobial Agents and Chemotherapy 11/2010; 54(11):4636-42. · 4.84 Impact Factor
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ABSTRACT: We determined the in vitro MIC of arbekacin against 200 Acinetobacter isolates recovered from wounded soldiers. The median MIC was 2 microg/ml (range, 0.5 to > 64 microg/ml). A total of 97.5% of the isolates had arbekacin MICs of < 8 microg/ml and 86.5% had MICs of < or = 4 microg/ml. There was no association between the arbekacin MIC and susceptibility to 16 other antibiotics or the specimen source (P = 0.7239). Synergy testing suggested an enhanced effect of arbekacin-carbapenem combinations.
Antimicrobial Agents and Chemotherapy 07/2010; 54(7):3015-7. · 4.84 Impact Factor
