Development of a nebramine-cyclam conjugate as an antibacterial adjuvant to potentiate β-lactam antibiotics against multidrug-resistant P. aeruginosa

Ammeter, Derek; Idowu, Temilolu; Zhanel, George G.; Schweizer, Frank

doi:10.1038/s41429-019-0221-9

Cited by 20 publications

(18 citation statements)

References 40 publications

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“…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 ].…”

Section: Discussionmentioning

confidence: 99%

“…The NEB-cyclam conjugate 60 ( Figure 11 ) was shown to potentiate β-lactam antibiotics, as well as other antibiotic drugs, against P. aeruginosa in vitro [ 116 ]. This adjuvant is able to synergize with β-lactams aztreonam and ceftazidime against MDR and extremely drug-resistant clinical isolates through a hypothesized mechanism of OM permeabilization.…”

Section: Antibacterial Amphiphilic Aminoglycosides (Antibacterial mentioning

confidence: 99%

“…The TOB-cyclam conjugate 59 (n = 8) mitigates the effect of OprD/OprF porin loss in P. aeruginosa and potentiates β-lactam/βlactamase inhibitors against carbapenem-resistant clinical isolates, highlighting the complexity of resistance to β-lactam antibiotics. [115] and 60 [116].…”

Section: Recent Reports On Aags In the Field Of Antibacterial Agentsmentioning

confidence: 99%

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Amphiphilic Aminoglycosides as Medicinal Agents

Dezanet

Kempf

Mingeot‐Leclercq

et al. 2020

IJMS

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Antibacterial Amphiphilic Aminoglycosides (Antibacterial mentioning

confidence: 99%

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Amphiphilic Aminoglycosides as Medicinal Agents

Dezanet

Kempf

Mingeot‐Leclercq

et al. 2020

IJMS

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“…A hybrid of ciprofloxacin-cyclam analog was designed to improve the activity against multidrug-resistant Gram-negative bacteria, especially multidrug-resistant phenotypes developed by Pseudomonas aeruginosa by reducing permeability and/or overexpressed efflux pumps. The antibacterial results revealed that conjugate 117 exhibited antibacterial activities with (MIC, 32, 4, and 1 μg/ml) against efflux deficient mutant strains of P, aeruginosa, PAO1, PAO200, and PAO750 respectively [145].…”

Section: Antimicrobial Activitymentioning

confidence: 99%

Recent Strategies in Design of Antitumor and Antibacterial Fluoroquinolones

Samir

Ramadan

Hamed

et al. 2021

Journal of advanced Biomedical and Pharmaceutical Sciences

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Fluoroquinolones are known widely used synthetic antibacterial agents. Generally, there were some obstacles associated with their therapeutic use. Moreover, many research studies all over the world proved the variable biological effects of fluoroquinolones such as antituberculosis, anticancer, or even antiviral activities. The current review is focused on modifications that occurred in the fluoroquinolone scaffold for their repositioning from antibacterial into anticancer agents especially modifications at C-7 or at the carboxylic C-3 groups. In addition, it includes the recent research studies carried out to improve the potency, spectrum of activity, or pharmacokinetics of antibacterial fluoroquinolones. Hence, this review may be useful for researchers in the design and synthesis of new fluoroquinolones with improved biological activities.

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“…Combinations with cefuroxime and chloramphenicol increased the antibiotic activity against MRSA and caused a several-fold reduction in MIC for cefuroxime (up to 8192-fold) and chloramphenicol (up to 64-fold) (Chan et al, 2017). Several other compounds, such as Nebramine-cyclam and EDTA, have also shown synergistic effects with antibiotics against P. aeruginosa (Ammeter et al, 2019;Maisetta et al, 2020).…”

Section: Combinatorial Treatments To Combat Multidrug Resistancementioning

confidence: 99%

Current Trends in Experimental and Computational Approaches to Combat Antimicrobial Resistance

et al. 2020

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A multitude of factors, such as drug misuse, lack of strong regulatory measures, improper sewage disposal, and low-quality medicine and medications, have been attributed to the emergence of drug resistant microbes. The emergence and outbreaks of multidrug resistance to last-line antibiotics has become quite common. This is further fueled by the slow rate of drug development and the lack of effective resistome surveillance systems. In this review, we provide insights into the recent advances made in computational approaches for the surveillance of antibiotic resistomes, as well as experimental formulation of combinatorial drugs. We explore the multiple roles of antibiotics in nature and the current status of combinatorial and adjuvant-based antibiotic treatments with nanoparticles, phytochemical, and other non-antibiotics based on synergetic effects. Furthermore, advancements in machine learning algorithms could also be applied to combat the spread of antibiotic resistance. Development of resistance to new antibiotics is quite rapid. Hence, we review the recent literature on discoveries of novel antibiotic resistant genes though shotgun and expression-based metagenomics. To decelerate the spread of antibiotic resistant genes, surveillance of the resistome is of utmost importance. Therefore, we discuss integrative applications of whole-genome sequencing and metagenomics together with machine learning models as a means for state-of-the-art surveillance of the antibiotic resistome. We further explore the interactions and negative effects between antibiotics and microbiomes upon drug administration.

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Development of a nebramine-cyclam conjugate as an antibacterial adjuvant to potentiate β-lactam antibiotics against multidrug-resistant P. aeruginosa

Cited by 20 publications

References 40 publications

Amphiphilic Aminoglycosides as Medicinal Agents

Amphiphilic Aminoglycosides as Medicinal Agents

Recent Strategies in Design of Antitumor and Antibacterial Fluoroquinolones

Current Trends in Experimental and Computational Approaches to Combat Antimicrobial Resistance

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