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.

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The design, synthesis, and in vitro microbiological analysis of an array of forty covalently linked vancomycin dimers are reported. This work was undertaken to systematically probe the impact of linkage orientation and linker length on biological activity against susceptible and drug-resistant Gram-positive pathogens. To prepare the array, monomeric vancomycin synthons were linked through four distinct positions of the glycopeptide (C-terminus (C), N-terminus (N), vancosamine residue (V), and resorcinol ring (R)) in 10 unique pairwise combinations. Amphiphilic, peptide-based linkers of four different lengths (11, 19, 27, and 43 total atoms) were employed. Both linkage orientation and linker length were found to affect in vitro antibacterial potency. The V-V series displayed the greatest potency against vancomycin-susceptible organisms and vancomycin-resistant Enterococcus faecalis (VRE) of VanB phenotype, while the C-C, C-V, and V-R series displayed the most promising broad-spectrum activity that included VRE of VanA phenotype. Dimers bearing the shortest linkers were in all cases preferred for activity against VRE. The effects of linkage orientation and linker length on in vitro potency were not uniform; for example, (1) no single compound displayed activity that was superior against all test organisms to that of vancomycin or the other dimers, (2) linker length effects varied with test organism, and (3) whereas one-half of the dimers were more potent than vancomycin against methicillin-susceptible Staphylococcus aureus (MSSA), only one dimer was more potent against methicillin-resistant S. aureus (MRSA) and glycopeptide-intermediate susceptible S. aureus (GISA). In interpreting the results, we have considered the potential roles of multivalency and of other phenomena.

UDP‐3‐O‐(R‐3‐hydroxymyristoyl)‐N‐acetylglucosamine deacetylase (LpxC) is a Zn2+ deacetylase that is essential for the survival of most pathogenic Gram‐negative bacteria. ACHN‐975 (N‐((S)‐3‐amino‐1‐(hydroxyamino)‐3‐methyl‐1‐oxobutan‐2‐yl)‐4‐(((1R,2R)‐2‐(hydroxymethyl)cyclopropyl)buta‐1,3‐diyn‐1‐yl)benzamide) was the first LpxC inhibitor to reach human clinical testing and was discovered to have a dose‐limiting cardiovascular toxicity of transient hypotension without compensatory tachycardia. Herein we report the effort beyond ACHN‐975 to discover LpxC inhibitors optimized for enzyme potency, antibacterial activity, pharmacokinetics, and cardiovascular safety. Based on its overall profile, compound 26 (LPXC‐516, (S)‐N‐(2‐(hydroxyamino)‐1‐(3‐methoxy‐1,1‐dioxidothietan‐3‐yl)‐2‐oxoethyl)‐4‐(6‐hydroxyhexa‐1,3‐diyn‐1‐yl)benzamide) was chosen for further development. A phosphate prodrug of 26 was developed that provided a solubility of >30 mg mL−1 for parenteral administration and conversion into the active drug with a t1/2 of approximately two minutes. Unexpectedly, and despite our optimization efforts, the prodrug of 26 still possesses a therapeutic window insufficient to support further clinical development.

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 MIC 50 and MIC 90 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.