Amphiphilic nebramine-based hybrids Rescue legacy antibiotics from intrinsic resistance in multidrug-resistant Gram-negative bacilli

Interest of Homodialkyl Neamine Derivatives against Resistant P. aeruginosa, E. coli, and β-Lactamases-Producing Bacteria—Effect of Alkyl Chain Length on the Interaction with LPS

“…Huge efforts have been made in the RAS work from the aminoglycoside backbone, leading to appealing lead compounds with antifungal [36,37] or antibacterial activity [38][39][40][41]. Tobramycin [40], nebramine [42], and neamine [43] are the pseudo-oligosaccharide scaffolds most often used for the development of new amphiphilic aminoglycoside antibiotics. Our research focuses on the new amphiphilic derivative of neamine, which is able to bind to bacterial membranes, partition into the membrane-water interface, and alter the packing and organization of lipids and the activity of proteins involved in the cytokinesis and bacterial shape [24,29].…”

Amphiphilic Aminoglycosides as Medicinal Agents

“…In a promising strategy to combat bacterial resistance, antibacterial AAGs have also emerged as adjuvants in combination with existing antibiotics. AG conjugates to an efflux pump inhibitor or to an antibiotic drug of another class (antibiotic hybrids) can promote, as adjuvants, the uptake of antibiotics through the OM of Gram-negative bacteria via the self-promoted uptake mechanism by displacement of the divalent cations (Ca 2+ or Mg 2+ ), which stabilize LPS [ 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 ]. The high affinity of strongly lipophilic AAGs of the first and second types for nucleic acids was used to develop efficient non-antibacterial vehicles for nucleic acid uptake in mammalian cells [ 129 , 130 , 131 , 132 , 133 , 134 , 135 ].…”

“…In combination with the TOB-CIP hybrid 55 ( n = 12, Figure 10 ), the antibacterial activity of mitomycin C was enhanced against MDR clinical isolates of P. aeruginosa , A. baumannii , E. coli , K. pneumoniae and Enterobacter cloacae . Synergy was inherent to TOB-CIP and neither TOB nor CIP individually synergized with mitomycin C. The TOB-based hybrid adjuvants able to potentiate multiple classes of legacy antibiotics against various MDR Gram-negative bacteria were modified by replacing the TOB domain with the smaller pseudo-disaccharide NEB through selective cleavage of the α-D-glucopyranosyl linkage of TOB 8 , which is an NEA ( 7 ) analogue lacking the 3′-hydroxyl function ( Figure 2 and Figure 10 ) [ 112 ]. The hybrid AAGs NEB-moxifloxacin (NEB-MOX) 56 , NEB-ciprofloxacin (NEB-CIP) 57 and NEB-1-(1′-naphthylmethyl)piperazine (NEB-NMP) 58 were synthesized ( 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 ]. …”

Macrocycle-Antibiotic Hybrids: A Path to Clinical Candidates

“…Very recently, design and synthesis of vitamin B12-antibiotic conjugates led to advanced candidates with >500-fold improved activity against Gram-negative bacteria including E. coli, relative to ampicillin, demonstrating that the vitamin B12 conjugate strategy is effective for enabling cellular uptake and antibiotic delivery, thus improving antibacterial efficacy (Zhao et al, 2020). Furthermore, among numerous elegant examples by the Schweizer group (Gorityala et al, 2016a;Gorityala et al, 2016b;Yang et al, 2017;Domalaon et al, 2019), the use of antibiotic hybrids as adjuvants such as nebramine-based hybrids (Yang et al, 2019) and lysine-tobramycin conjugates (Lyu et al, 2019) has potentiated the activities of current existing antibiotics including rifampicin and erythromycin, respectively. Similarly, rifamycin-tobramycin conjugate adjuvants were able to break intrinsic resistance of Pseudomonas aeruginosa to tetracyclines and chloramphenicol (Idowu et al, 2019).…”