Modified aminoglycoside compounds and uses thereof in disabling bacterial ribosome

A compound represented by Formula I:

• or a pharmaceutically acceptable salt thereof,
• wherein:
• the dashed line indicates a stereo-configuration of position 6′ being an R configuration or an S configuration;
• X1 is O or S;
• Rx1, Rx2, Ry1 and Rz are each independently selected from hydrogen, alkyl and cycloalkyl;
• Ry2-Ry9 and Rw1-Rw3 are each independently selected from hydrogen, alkyl, and cycloalkyl;
• R1, R3 and R4 are each independently NR23R24, OR20 or a diamine-containing moiety, wherein R20 is hydrogen, alkyl, cycloalkyl or the diamine-containing moiety, and each of R23 and R24 is independently hydrogen, alkyl, cycloalkyl or acyl, provided that at least one of R1, R3 and R4 is or comprises the diamine-containing moiety;
• R5 and R6 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalicyclic, aryl, heteroaryl and OR16, wherein Rib is independently selected from hydrogen, a monosaccharide moiety and an oligosaccharide moiety;
• and
• R7-R9 are each independently selected from the group consisting of hydrogen and acyl,
• wherein said diamine-containing moiety comprises at least two amine-containing groups and at least one linking group linking said at least two amine-containing groups, and wherein said amine-containing groups and said at least one linking group are arranged such that:
• (i) a difference in the pKa of at least two of said amine-containing groups is at least 1;
• and/or
• (ii) when the compound is in a physiological environment, at least one of said amine-containing groups is protonated at physiological pH while at least another of said amine-containing groups is non-protonated;
• and/or
• (iii) when the compound interacts with a prokaryotic ribosomal RNA decoding site (A-site), the RNA undergoes a conformational change such that an O—P—O angle of at least one phosphodiester bond is higher than 100°;
• and/or
• (iv) when the compound interacts with a prokaryotic ribosomal RNA decoding site (A-site), the functional moiety is capable of adopting a configuration in which one of said amine-containing groups is in close proximity and suitable orientation so as to interact with a 2′-OH group of a ribose of a nucleotide in said RNA and another amine-containing moiety is in close proximity and suitable orientation so as to interact with a phosphate group of a nucleotide of an adjacent nucleotide.