Synthesis and Spectrum of the Neoglycoside ACHN-490

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 Grampositive 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 g/ml), with the exception of Proteus mirabilis and indole-positive Proteae (MIC 90 , 8 g/ml and 16 g/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 g/ml. Due to its promising in vitro and in vivo profiles, ACHN-490 has been advanced into clinical development as a new antibacterial agent.

Carbapenem-Resistant Klebsiella pneumoniae Strains Exhibit Diversity in Aminoglycoside-Modifying Enzymes, Which Exert Differing Effects on Plazomicin and Other Agents

“…AAC(3)-IV is known to confer gentamicin and tobramycin resistance among clinical strains of Escherichia coli (35), but to our knowledge, it has not been reported previously in K. pneumoniae or significantly associated with higher plazomicin MICs. Our findings suggest that the 1-Nhydroxyaminobutyric acid within plazomicin may not confer full protection from inactivation by AAC(3)-IV (12). APH(3=)-Ia cannot modify plazomicin because the drug lacks the target 3=-OH group, and it has not been linked to resistance to any of the agents in this study.…”

“…Plazomicin, a derivative of sisomicin, is a next-generation aminoglycoside that is in clinical development for the treatment of serious infections due to carbapenem-resistant Enterobacteriaceae. It has broad-spectrum in vitro activity against Klebsiella pneumoniae and other Gram-negative bacteria, including carbapenem-resistant strains (8)(9)(10)(11)(12). The agent has side-chain substituents that shield it from the action of most AMEs.…”

Synthesis and Biological Activity of Mono- and Di-N-acylated Aminoglycosides

“…6′-N-Cbz-TOB (20) was prepared from the reaction of TOB and compound 3, using potassium carbonate as a base in a 1:1 mixture of H 2 O and MeOH. It is important to note that an attempt at using O-Cbz-N-hydroxysuccinimide instead of compound 3, did not yield any of the desired compound 20.…”

“…They were also moderately active (MIC = 8 μg/mL) against S. aureus ATCC 29213 (E). Testing of the 6′-N-Cbz-TOB (20) suggested that having an amine in the group added to the parent AG scaffold is greatly beneficial as 20 was found to be inactive against almost all bacterial strains tested.…”

“…The development of semisynthetic AGs has proven a successful strategy for overcoming, to some extent, the AG resistance problem. In particular, the incorporation of a γ-amino-β-hydroxybutyric acid (AHB), exemplified by plazomicin 20 and amikacin (AMK), or a glycinyl group to the scaffold of known AGs has been one successful strategy used to circumvent AMEs while retaining or improving upon their antibacterial properties. 21 The synthesis of complex carbohydrates like AGs, which comprise two to five individual sugars, is often a daunting task, and their total synthesis from basic chemical building blocks is rarely an efficient means of developing novel, effective compounds.…”