Design, Synthesis, and Evaluation of Fimbrolide–Nitric Oxide Donor Hybrids as Antimicrobial Agents

Kutty, Samuel K.; Barraud, Nicolas; Pham, Anh; Iskander, George M.; Rice, Scott A.; Black, David StC.; Kumar, Naresh

doi:10.1021/jm400951f

Cited by 48 publications

(39 citation statements)

References 34 publications

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“…This highlights an ongoing concern for polymicrobial biofilms infections. Other drugs that are currently under development include ciprofloxacin-nitroxide conjugates, which similar to C3Ds, combine antibiotic activity with a donor compound 76 , and fimbrolide-NO donor hybrids, which simultaneously target quorum sensing (QS) and NO pathways 77 .…”

Section: Inducing Biofilm Dispersalmentioning

confidence: 99%

Targeting microbial biofilms: current and prospective therapeutic strategies

et al. 2017

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Biofilm formation is a key virulence factor for a wide range of microorganisms that cause chronic infections. The multifactorial nature of biofilm development and drug tolerance imposes great challenges for the use of conventional antimicrobials, and indicates the need for multi-targeted or combinatorial therapies. In this review, we focus on current therapeutic strategies and those that are under development that target vital structural and functional traits of microbial biofilms and drug tolerance mechanisms, including the extracellular matrix and dormant cells. We emphasize strategies that are supported by in vivo or ex vivo studies, highlight emerging biofilm-targeting technologies, and provide a rationale for multi-targeted therapies that are aimed at disrupting the complex biofilm microenvironment.

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Section: Inducing Biofilm Dispersalmentioning

confidence: 99%

Targeting microbial biofilms: current and prospective therapeutic strategies

et al. 2017

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“…However, the antimicrobial activity of this class of bioactive compounds has not been investigated. There is only one recent report by Kutty et al . on nitrate esters possessing strong biofilm inhibition activity.…”

Section: Introductionmentioning

confidence: 99%

Nitrate Esters of Heteroaromatic Compounds as Candida albicans CYP51 Enzyme Inhibitors

et al. 2018

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Four heteroaromatic compounds bearing nitrate esters were selected using a virtual-screening procedure as putative sterol 14α-demethylase (CYP51) Candida albicans inhibitors. Compounds were examined for their inhibition on C. albicans growth and biofilm formation as well as for their toxicity. NMR spectroscopy studies, in silico docking, and molecular dynamics simulations were used to investigate further the selectivity of these compounds to fungal CYP51. All compounds exhibited good antimicrobial properties, indicated with low minimal inhibitory concentrations and ability to inhibit formation of fungal biofilm. Moreover, all of the compounds had the ability to inhibit growth of C. albicans cells. N-(2-Nitrooxyethyl)-1Η-indole-2-carboxamide was the only compound with selectivity on C. albicans CYP51 that did not exhibit cytotoxic effect on cells isolated from liver and should be further investigated for selective application in new leads for the treatment of candidiasis.

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“…Recently, novel dual-action furanone-NO donor hybrid compounds have been designed and synthesized. Two compounds were found to have both QS inhibition and NO releasing properties and were effective antibiofilm agents [147]. …”

mentioning

confidence: 99%

Nitric Oxide: A Key Mediator of Biofilm Dispersal with Applications in Infectious Diseases

Barraud¹,

Kelso²,

Rice

et al. 2014

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Studies of the biofilm life cycle can identify novel targets and strategies for improving biofilm control measures. Of particular interest are dispersal events, where a subpopulation of cells is released from the biofilm community to search out and colonize new surfaces. Recently, the simple gas and ubiquitous biological signaling molecule nitric oxide (NO) was identified as a key mediator of biofilm dispersal conserved across microbial species. Here, we review the role and mechanisms of NO mediating dispersal in bacterial biofilms, and its potential for novel therapeutics. In contrast to previous attempts using high dose NO aimed at killing pathogens, the use of low, non-toxic NO signals (picomolar to nanomolar range) to disperse biofilms represents an innovative and highly favourable approach to improve infectious disease treatments. Further, several NO-based technologies have been developed that offer a versatile range of solutions to control biofilms, including: (i) NO-generating compounds with short or long half-lives and safe or inert residues, (ii) novel compounds for the targeted delivery of NO to infectious biofilms during systemic treatments, and (iii) novel NO-releasing materials and surface coatings for the prevention and dispersal of biofilms. Overall the use of low levels of NO exploiting its signaling properties to induce dispersal represents an unprecedented and promising strategy for the control of biofilms in clinical and industrial contexts. AbstractStudies of the biofilm life cycle can identify novel targets and strategies for improving biofilm control measures. Of particular interest are dispersal events, where a subpopulation of cells is released from the biofilm community to search out and colonize new surfaces. Recently, the simple gas and ubiquitous biological signaling molecule nitric oxide (NO) was identified as a key mediator of biofilm dispersal conserved across microbial species. Here, we review the role and mechanisms of NO mediating dispersal in bacterial biofilms, and its potential for novel therapeutics. In contrast to previous attempts using high dose NO aimed at killing pathogens, the use of low, non-toxic NO signals (picomolar to nanomolar range) to disperse biofilms represents an innovative and highly favourable approach to improve infectious disease treatments. Further, several NO-based technologies have been developed that offer a versatile range of solutions to control biofilms, including: (i) NO-generating compounds with short or long half-lives and safe or inert residues, (ii) novel compounds for the targeted delivery of NO to infectious biofilms during systemic treatments, and (iii) novel NO-releasing materials and surface coatings for the prevention and dispersal of biofilms. Overall the use of low levels of NO exploiting its signaling properties to induce dispersal represents an unprecedented and promising strategy for the control of biofilms in clinical and industrial contexts. 3 Increased antimicrobial tolerance in biofilms is the basis for chronic infecti...

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Design, Synthesis, and Evaluation of Fimbrolide–Nitric Oxide Donor Hybrids as Antimicrobial Agents

Cited by 48 publications

References 34 publications

Targeting microbial biofilms: current and prospective therapeutic strategies

Targeting microbial biofilms: current and prospective therapeutic strategies

Nitrate Esters of Heteroaromatic Compounds as Candida albicans CYP51 Enzyme Inhibitors

Nitric Oxide: A Key Mediator of Biofilm Dispersal with Applications in Infectious Diseases

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