Amphiphilic Aminoglycosides as Medicinal Agents

Abstract

The conjugation of hydrophobic group(s) to the polycationic hydrophilic core of the antibiotic drugs aminoglycosides (AGs), targeting ribosomal RNA, has led to the development of amphiphilic aminoglycosides (AAGs). These drugs exhibit numerous biological effects, including good antibacterial effects against susceptible and multidrug-resistant bacteria due to the targeting of bacterial membranes. In the first part of this review, we summarize our work in identifying and developing broad-spectrum antibacterial AAGs that constitute a new class of antibiotic agents acting on bacterial membranes. The target-shift strongly improves antibiotic activity against bacterial strains that are resistant to the parent AG drugs and to antibiotic drugs of other classes, and renders the emergence of resistant Pseudomonas aeruginosa strains highly difficult. Structure-activity and structure-eukaryotic cytotoxicity relationships, specificity and barriers that need to be crossed in their development as antibacterial agents are delineated, with a focus on their targets in membranes, lipopolysaccharides (LPS) and cardiolipin (CL), and the corresponding mode of action against Gram-negative bacteria. At the end of the first part, we summarize the other recent advances in the field of antibacterial AAGs, mainly published since 2016, with an emphasis on the emerging AAGs which are made of an AG core conjugated to an adjuvant or an antibiotic drug of another class (antibiotic hybrids). In the second part, we briefly illustrate other biological and biochemical effects of AAGs, i.e., their antifungal activity, their use as delivery vehicles of nucleic acids, of short peptide (polyamide) nucleic acids (PNAs) and of drugs, as well as their ability to cleave DNA at abasic sites and to inhibit the functioning of connexin hemichannels. Finally, we discuss some aspects of structure-activity relationships in order to explain and improve the target selectivity of AAGs.

Keywords: aminoglycosides; amphiphilic; antibacterial; antibiotic; cardiolipin; delivery vehicles; lipopolysaccharides; membranes.

Figure 1

Structures of natural antibiotic aminoglycosides 1–5, of some corresponding constitutive derivatives 6–8 and of synthetic intermediates used to prepare amphiphilic aminoglycosides (AAGs) 9–13 (Tr = trityl group = triphenylmethyl, PMB = para-methoxyphenyl group).

Figure 2

Structure of polymyxin E (COL), showing the five amine functions protonated at physiological pH.

Figure 3

Structures of the first identified broad-spectrum antibacterial amphiphilic neamine (NEA) (6) and paromamine (PARA) (7) derivatives [5,34].

Figure 4

Structures of the identified broad-spectrum antibacterial amphiphilic dialkyl (24 and 25) and dialkylnaphthyl (26–28) NEA derivatives [34].

Figure 5

Structures of the broad-spectrum antibacterial 3′,4′-dinonyl NEA derivative and of the corresponding antibacterial analogues synthesized in the 1-methyl neosamine series [36].

Figure 6

Structures of antibacterial homodialkyl (38–41, 46, 47) and heterodialkyl (42–45) NEA derivatives synthesized [35].

Figure 7

Values of 1/(MIC (mL/µg) as a function of clogP values for 3′,6-dinaphthylalkyl NEAs (di2NM 14, di2NP 26, di2NB 27 and di2-naphthylhexyl) and 3′,6-dialkyl NEAs (diC4, diC6, diC7 38, diC8 39, diC9 24, diC10 40, diC11 41 and diC18). (A) Against MRSA; (B) against susceptible P. aeruginosa ATCC 27853. Naphthylalkyl derivatives: red squares; alkyl derivatives: green triangles [35].

Figure 8

Comparison of the structures of lipid A and cardiolipin (CL) to the structure of the antibacterial 3′,6-dinonyl NEA derivative 24.

Figure 9

Structures of the tobramycin (TOB) conjugates to lysine 48 [105,106], and to the efflux pump inhibitors (EPIs), 1-(1′-naphthylmethyl)piperazine (NMP) (49), paroxetine (PAR) (50) and dibasic naphthyl peptide (DBP) (51) [107,108].

Figure 10

Structures of the TOB (52–54) and nebramine (NEB) (56) conjugates to the fluoroquinolones moxifloxacin (MOX) and ciprofloxacin (CIP) [109,111], respectively 55 and 57, and, of the NEB conjugates to the efflux pump inhibitor 1-(1′-naphthylmethyl)piperazine (NEB-NMP) 58 [112].

Figure 11

Structures of the TOB-cyclam and NEB-cyclam hybrids 59 [115] and 60 [116].

Figure 12

Structures of the synthesized broad-spectrum antibacterial 4′,5,6-tri- and 4′,5-di-alkylated NEB derivatives [37,38].

Figure 13

Structure of the amphiphilic aminoglycoside K20, capable of inhibiting many fungal species such as Fusarium graminearum, the causal agent wheat Fusarium head blight (FHB) [125,126,127,128].

Figure 14

Structure of one of the kanamycin (KANA)-cholesterol conjugates, 61, developed for gene transfection [130].

Figure 15

Structures of the most efficient NEA-based vectors for gene transfection [134].

Figure 16

Structures of the AAGs developed for small interfering RNA (siRNA) delivery made of the TOB, KANA, PARO and NEO cores, respectively, linked to two dioleyl chains by a succinyl spacer [135].

Figure 17

Structures of the anti-HIV (anti-TAR RNA) PNA conjugates to NEA [145,149] and to 6-amino-6-deoxy-1-methylglucosamine (1-methyl neosamine) [151].

Figure 18

Structure of the most efficient DNA-cleaving AAG identified, 76, at abasic sites [157], and of the amphiphilic azobenzene-NEO conjugate 77 forming nanostructures [158].

Figure 19

Structures of AAGs that are non-bactericidal and non-toxic or moderately toxic to mammalian HeLa cells, which are connexin hemichannel (HC) inhibitors [160].