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Aminoglycosides are broad-spectrum antibiotics with particular clinical utility against life-threatening infections. As resistance to antibiotics, including aminoglycosides, continues to grow, there is a need for new and effective antimicrobial agents. ACHN-490 is a novel aminoglycoside in clinical development with activity against multidrug-resistant Gram-negative and select Gram-positive pathogens. Here we assess the in vivo efficacy of ACHN-490 against a variety of common pathogens in two murine models: the septicemia and neutropenic thigh models. When its activity against a gentamicin-susceptible strain of Escherichia coli was tested in the septicemia model, ACHN-490 improved 7-day survival with a dose-response profile similar to that of gentamicin, with 100% survival seen at doses of 1.6 mg/kg of body weight and above. In animals infected with a gentamicin-susceptible strain of Pseudomonas aeruginosa, treatment with either ACHN-490 or gentamicin led to 100% survival at doses of 16 mg/kg and above in the septicemia model. ACHN-490 was also effective in the neutropenic thigh model, reducing multidrug-resistant Enterobacteriaceae family and methicillin-resistant Staphylococcus aureus strains, as well as broadly susceptible strains, to static levels with dose-dependent activity. Against gentamicin-sensitive Enterobacteriaceae and methicillin-resistant S. aureus, the efficacy of ACHN-490 was comparable to that of gentamicin. However, gentamicin-resistant Enterobacteriaceae strains and those harboring the Klebsiella pneumoniae carbapenemase responded to ACHN-490 but not gentamicin, with static doses ranging from 12 mg/kg to 64 mg/kg for ACHN-490. These results suggest that ACHN-490 has the potential to become a clinically useful agent against drug-resistant pathogens, including Enterobacteriaceae, P. aeruginosa, and methicillin-resistant S. aureus, and support further development of this promising novel aminoglycoside.

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.

The in vitro activity of ACHN-490, a novel aminoglycoside ("neoglycoside"), was evaluated against 102 multidrug-resistant (MDR) Klebsiella pneumoniae strains, including a subset of 25 strains producing the KPC carbapenemase. MIC50 values for gentamicin, tobramycin, and amikacin were 8 microg/ml, 32 microg/ml, and 2 microg/ml, respectively; MIC90 values for the same antimicrobials were > or = 64 microg/ml, > or = 64 microg/ml, and 32 microg/ml, respectively. ACHN-490 showed an MIC50 of 0.5 microg/ml and an MIC90 of 1 microg/ml, which are significantly lower than those of comparator aminoglycosides. ACHN-490 represents a promising aminoglycoside for the treatment of MDR K. pneumoniae isolates, including those producing KPC beta-lactamase.