Design, synthesis and biological activity evaluation of novel 4-subtituted 2-naphthamide derivatives as AcrB inhibitors

Wang, Yinhu; Mowla, Rumana; Ji, Shengli; Guo, Liwei; Lopes, Miguel de Barros; Jin, Chaobin; Song, Di; Ma, Shutao; Venter, Henrietta

doi:10.1016/j.ejmech.2017.11.102

Cited by 40 publications

(28 citation statements)

References 39 publications

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“…Bacteria can be intrinsically resistant to antibiotics or develop resistance rapidly after exposure to antibiotics ( Blair et al, 2015 ). The mechanisms of antibiotic resistance are generally developed through the following pathways: (i) bacteria producing specific enzyme to inactivate antibacterial drugs ( Lin et al, 2015 ); (ii) modifying drug targets to render antibiotics ineffective ( Walsh, 2003 ; Mi et al, 2016 ); (iii) changing the permeability of the outer membrane to prevent drugs entering the cell body, affecting the efflux system to pump out the drugs ( Walsh, 2003 ; Nikaido and Pagès, 2012 ; Wang et al, 2018 ). Therefore, new generation of antibacterial agents that act through novel mechanisms and/or on novel targets are needed ( Payne, 2008 ; Rice, 2008 ).…”

Section: Introductionmentioning

confidence: 99%

Study of Benzofuroquinolinium Derivatives as a New Class of Potent Antibacterial Agent and the Mode of Inhibition Targeting FtsZ

Zheng

Cai

et al. 2018

Front. Microbiol.

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New generation of antibacterial agents are urgently needed in order to fight the emergence of multidrug-resistant bacteria. FtsZ is currently identified as a promising target for new types of antimicrobial compounds development because of its conservative characteristics and its essential role played in bacterial cell division. In the present study, the antibacterial activity of a series of benzofuroquinolinium derivatives was investigated. The results show that the compounds possess potent antibacterial activity against drug resistant pathogens including MRSA, VREF and NDM-1 Escherichia coli. Biological studies reveal that the compound is an effective inhibitor that is able to suppress FtsZ polymerization and GTPase activity and thus stopping the cell division and causing cell death. More importantly, this series of compounds shows low cytotoxicity on mammalian cells and therefore they could be new chemotypes for the development of new antibacterial agents targeting the cell-division protein FtsZ.

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Section: Introductionmentioning

confidence: 99%

Study of Benzofuroquinolinium Derivatives as a New Class of Potent Antibacterial Agent and the Mode of Inhibition Targeting FtsZ

Zheng

Cai

et al. 2018

Front. Microbiol.

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“…MICs of biocides and antimicrobials in the presence of the efflux pump inhibitor, phenylalanine arginine β-naphthylamide (PAβN) (Sigma-Aldrich, St. Louis, Missouri, USA) were determined using a checkerboard assay following the steps outlined in a previous study [47]. Only strains that were resistant to FQs (MIC of ciprofloxacin ≥ 1 mg/L and levofloxacin ≥ 2 mg/L) as well as benzalkonium chloride (MIC ≥ 128 mg/L) and triclosan (MIC ≥ 512 mg/L) were subjected to the checkerboard assay in the presence of efflux pump inhibitors.…”

Section: Efflux Pump Inhibition Using a Checkerboard Assaymentioning

confidence: 99%

Efflux Pump-Driven Antibiotic and Biocide Cross-Resistance in Pseudomonas aeruginosa Isolated from Different Ecological Niches: A Case Study in the Development of Multidrug Resistance in Environmental Hotspots

et al. 2020

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Pseudomonas aeruginosa is an opportunistic pathogen displaying high intrinsic antimicrobial resistance and the ability to thrive in different ecological environments. In this study, the ability of P. aeruginosa to develop simultaneous resistance to multiple antibiotics and disinfectants in different natural niches were investigated using strains collected from clinical samples, veterinary samples, and wastewater. The correlation between biocide and antimicrobial resistance was determined by employing principal component analysis. Molecular mechanisms linking biocide and antimicrobial resistance were interrogated by determining gene expression using RT-qPCR and identifying a potential genetic determinant for co- and cross-resistance using whole-genome sequencing. A subpopulation of P. aeruginosa isolates belonging to three sequence types was resistant against the common preservative benzalkonium chloride and showed cross-resistance to fluoroquinolones, cephalosporins, aminoglycosides, and multidrug resistance. Of these, the epidemiological high-risk ST235 clone was the most abundant. The overexpression of the MexAB-OprM drug efflux pump resulting from amino acid mutations in regulators MexR, NalC, or NalD was the major contributing factor for cross-resistance that could be reversed by an efflux pump inhibitor. This is the first comparison of antibiotic-biocide cross-resistance in samples isolated from different ecological niches and serves as a confirmation of laboratory-based studies on biocide adapted isolates. The isolates from wastewater had a higher incidence of multidrug resistance and biocide-antibiotic cross-resistance than those from clinical and veterinary settings.

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“…EDTA treatment leads to a release of LPS which is then compensated for by an increase in glycerophospholipids, resulting in patches of phospholipid bilayer with increased permeability to lipophilic compounds [76]. We have already showed that OM permeabilisation with sub-toxic concentrations of EDTA could enhance efficacy of an EPI by several fold [67] and that a Gram-positive selective new antibiotic also displayed Gram-negative activity in the presence of EDTA [92]. The safety profile of EDTA by itself is well-established as intravenous EDTA-chelation therapy is used to treat lead poisoning [93] and an EDTA chelation therapy regimen has been trailed to determine its safety and efficacy for individuals with prior heart attacks [94].…”

Section: Om Permeabilisersmentioning

confidence: 99%

“…The best studied example of an EPI against the tripartite antibiotic efflux pump of Gram-negative organisms is phenylarginyl-β-naphthylamide (PAβN), a simple naphthylamide peptide which did not progress beyond clinical trials due to toxicity [63]. Recent activity in this field by our group and others led to the design and synthesis of several compounds with increased efficacy [64][65][66][67] and low cytotoxicity [68].…”

Section: (Ii) Efflux Pump Inhibitorsmentioning

confidence: 99%

“…EDTA is a well-known metal chelator that can cause OM permeabilisation [90] and is widely used to study e.g. bioenergetics in Gram-negative bacteria [91] and for dye-based methods to confirm IM integrity [67,68]. EDTA treatment leads to a release of LPS which is then compensated for by an increase in glycerophospholipids, resulting in patches of phospholipid bilayer with increased permeability to lipophilic compounds [76].…”

Section: Om Permeabilisersmentioning

confidence: 99%

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Reversing resistance to counter antimicrobial resistance in the World Health Organisation’s critical priority of most dangerous pathogens

Venter

2019

Bioscience Reports

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The speed at which bacteria develop antimicrobial resistance far outpace drug discovery and development efforts resulting in untreatable infections. The World Health Organisation recently released a list of pathogens in urgent need for the development of new antimicrobials. The organisms that are listed as the most critical priority are all Gram-negative bacteria resistant to the carbapenem class of antibiotics. Carbapenem resistance in these organisms is typified by intrinsic resistance due to the expression of antibiotic efflux pumps and the permeability barrier presented by the outer membrane, as well as by acquired resistance due to the acquisition of enzymes able to degrade β-lactam antibiotics. In this perspective article we argue the case for reversing resistance by targeting these resistance mechanisms – to increase our arsenal of available antibiotics and drastically reduce antibiotic discovery times – as the most effective way to combat antimicrobial resistance in these high priority pathogens.

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Design, synthesis and biological activity evaluation of novel 4-subtituted 2-naphthamide derivatives as AcrB inhibitors

Cited by 40 publications

References 39 publications

Study of Benzofuroquinolinium Derivatives as a New Class of Potent Antibacterial Agent and the Mode of Inhibition Targeting FtsZ

Study of Benzofuroquinolinium Derivatives as a New Class of Potent Antibacterial Agent and the Mode of Inhibition Targeting FtsZ

Efflux Pump-Driven Antibiotic and Biocide Cross-Resistance in Pseudomonas aeruginosa Isolated from Different Ecological Niches: A Case Study in the Development of Multidrug Resistance in Environmental Hotspots

Reversing resistance to counter antimicrobial resistance in the World Health Organisation’s critical priority of most dangerous pathogens

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