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Amphiphilic Aminoglycosides As Medicinal Agents

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Amphiphilic Aminoglycosides As Medicinal Agents International Journal of Molecular Sciences Review Amphiphilic Aminoglycosides as Medicinal Agents Clément Dezanet 1, Julie Kempf 1, Marie-Paule Mingeot-Leclercq 2,* and Jean-Luc Décout 1,* 1 Molecular Pharmacochemistry Department, University Grenoble Alpes, CNRS, 470 Rue de la Chimie, F-38000 Grenoble, France; [email protected] (C.D.); [email protected] (J.K.) 2 Cellular and Molecular Pharmacology Unit, Louvain Drug Research Institute, Catholic University of Louvain, Avenue E. Mounier 73, UCL B1.73.05, 1200 Brussels, Belgium * Correspondence: [email protected] (M.-P.M.-L.); [email protected] (J.-L.D.) Received: 6 September 2020; Accepted: 2 October 2020; Published: 8 October 2020 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 1. Introduction Aminoglycosides (AGs), for example, neomycin B (NEO) 1, paromomycin (PARO) 2, kanamycins A and B (KANA, KANB) 3, 4 and tobramycin 5 (Figure1), constitute a large family of highly potent broad-spectrum antibiotic drugs. These naturally occurring hydrophilic pseudo-oligosaccharides, which are polycationic species at physiological pH, target ribosomal RNA and disrupt protein synthesis [1]. Unfortunately, the widespread clinical use of AGs has strongly reduced their clinical efficacy through the selection of resistant bacteria [2]. In the search for new antibacterial agents targeting bacterial membranes, our team and others have synthesized and identified antibacterial amphiphilic aminoglycosides (antibacterial AAGs), which constitute a new class of polycationic antibiotic agents [3–8]. AAGs can be defined as substances made of a hydrophilic AG core Int. J. Mol. Sci. 2020, 21, 7411; doi:10.3390/ijms21197411 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 7411 2 of 37 Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 2 of 36 on which lipophilic/hydrophobic group(s) are grafted, to produce, at physiological pH, cationic core on which lipophilic/hydrophobic group(s) are grafted, to produce, at physiological pH, cationic amphiphilic species. amphiphilic species. Ring II 6' R Ring II NH2 4' 5' O Ring I: Deoxystreptamine HO O (2DOS) HO HO H N R 2' 1' 2 2 H2N 3' NH2 3 2 R O 1 NH O NH HO O 2 HO 2 6 O 5 OH 1 6 O OH HO NH 2 HO O O OH OH H2N Ring III H2N O OH 1: Neomycin B: R= NH2 3: Kanamycin A: R1= R2= OH 2: Paromomycin: R= OH 4: Kanamycin B: R1= OH, R2= NH2, R3= H 5: Tobramycin: R1= NH2, R2= R3= H Ring II R1 R1 4' 6' O O HO R4O R2 R3O H2N TrHN NH2 3' O NHTrO HO NH2 HO NHTr 5 2 OH 6 OR 1 2 9: R1= NHTr, R2= R3= R4= H 6: Neamine: R = NH2, R = OH 1 2 3 4 7: Paromamine: R1= OH, R2= OH 10: R = NHTr, R = R = PMB, R = H 1 2 11: R1= NHTr, R2= R3= R4= PMB 8: Nebramine: R = NH2, R = H 12: R1= NHTr, R2= PMB, R3= R4= H 1 2 3 4 13: R = OTr, R = R = R = H Figure 1. Structures of natural antibiotic aminoglycosides 1–5,, of some correspondingcorresponding constitutive derivatives 6–8 and of synthetic intermediates used used to to prepare prepare amphiphilic aminoglycosides aminoglycosides (AAGs) (AAGs) 9–13 (Tr = trityltrityl group group = triphenylmethyl,triphenylmethyl, PMB PMB == parapara-methoxyphenyl-methoxyphenyl group). group). Originally, AAGsAAGs were were developed developed in thein searchthe search for new for AGsnew that AGs are that less susceptibleare less susceptible to resistance. to resistance.In this approach, In this Hanessian,approach, Hanessian, Westhof and Westhof coworkers and reported coworkers the reported first example the first of in example vivo antibacterial of in vivo antibacteriallipophilic ether-modified lipophilic ether-mo derivativesdified of PAROderivatives targeting of PARO ribosomal targeting RNA ribosomal with a novel RNA mode with of binding,a novel modewhich of are binding, able to inhibitwhich are AG-deactivating able to inhibit enzymes AG-deactivating [9,10]. enzymes [9,10]. InIn the never-ceasing fight fight against pathogenic multidrug-resistantmultidrug-resistant bacteria, the identification identification of new targets,targets, andand of of the the corresponding corresponding drugs, drugs, is imperative is imperative [11], and[11], an and interest an interest in membrane-targeting in membrane- targetingdrug is emerging drug is emerging [12]. The [12]. expected The expected major advantages major advantages of such drugsof such are drugs (i) their are (i) activity their activity against againstbacterial bacterial persisters persisters and antibiotic-tolerant and antibiotic-tolerant bacterial bacterial populations populations [13], characterized [13], characterized by a low metabolicby a low metabolicactivity [14 activity,15]; (ii) [14,15]; their low (ii) tendency their low for tendency the development for the development of bacterial of resistance bacterial [ 16resistance]; and (iii) [16]; the and fact (iii)that the they fact do notthat need they todo cross not theneed bacterial to cross outer the membranebacterial outer (OM) membrane of Gram-negative (OM) of bacteria.Gram-negative bacteria.Indeed, this mode of action should limit the emergence of resistance through drug modifications by intracellularIndeed, this resistance-causing mode of action should enzymes limit and the e emffluxergence pumps of expressed resistance by through multidrug-resistant drug modifications (MDR) bybacteria. intracellular Moreover, resistance-causing interaction with enzymes key membrane and efflux components, pumps expressed present in by multiple multidrug-resistant copies in the (MDR)bacterial bacteria. membranes, Moreover, can cause interaction many antibacterial with key membrane destructuring components, effects. The present bacteria in thatmultiple are resistant copies into the these bacterial effects membranes, have to perform can ca biochemicaluse many antibacterial modifications destructurin of multipleg membraneeffects. The componentsbacteria that [are17]. resistantThe corresponding to these metaboliceffects have modifications to perform have bi aochemical high energetic modifications cost for the selectedof multiple resistant membrane bacteria, componentsresulting in slow [17]. growth, The corresponding rapid reversibility metabolic of the emergingmodifications resistance have and a high high energetic sensitivity cost to antibiotic for the selecteddrugs of resistant other classes. bacteria, resulting in slow growth, rapid reversibility of the emerging resistance and highIn such sensitivity an approach, to antibiotic the antibacterial drugs of other potential classes. of cationic amphiphilic compounds that target bacterialIn such membranes an approach, is attractive the antibacterial from a drug potential development of cationic perspective. amphiphilic The compounds repurposing that of the target old bacterialantibacterial membranes cationic cyclopeptideis attractive from polymyxin a drug E,de colistinvelopment (COL, perspective. Figure2), acting The repurposing on the bacterial of the outer old antibacterialmembrane (OM), cationic as acyclopeptide last-line antibiotic polymyxin to treat E, colistin multidrug-resistant (COL, Figure (MDR) 2), acting Gram-negative on the bacterial bacterial outer membrane (OM), as a last-line antibiotic to treat multidrug-resistant (MDR) Gram-negative bacterial infections, especially those caused by antibiotic-resistant Pseudomonas aeruginosa strains, illustrate Int. J. Mol. Sci. 2020, 21, 7411 3 of 37 Int.infections, J. Mol. Sci. especially 2020, 21, x FOR those PEER caused REVIEW by antibiotic-resistant Pseudomonas aeruginosa strains, illustrate3 wellof 36 the interesting nature of cationic
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