Cephalosporin-3′-Diazeniumdiolate NO Donor Prodrug PYRRO-C3D Enhances Azithromycin Susceptibility of Nontypeable Haemophilus influenzae Biofilms

Collins, Samuel A.; Kelso, Michael J.; Rineh, Ardeshir; Yepuri, Nageshwar R.; Coles, Jonathan A.; Jackson, Claire; Halladay, Georgia D.; Walker, Woolf T.; Webb, Jeremy S.; Hall-Stoodley, Luanne; Connett, Gary; Feelisch, Martin; Faust, Saul N; Lucas, Jane S.; Allan, Raymond N.

doi:10.1128/aac.02086-16

Cited by 27 publications

(51 citation statements)

References 47 publications

(65 reference statements)

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“…These pro-drug candidates are designed to specifically release NO upon cleavage of the cephalosporin β-lactam ring via bacterial β-lactamases and have been shown to be effective in dispersing in vitro P. aeruginosa biofilms 71 . NTHi biofilms grown on primary ciliated epithelia also showed enhanced sensitivity to the antibiotic azithromycin, reducing viability 2-log when a specific C3D, PYRRO-C3D, was used as an adjuvant; this response is possibly attributable to dispersal and modulation of metabolic activity 72 . This effect was also demonstrated in a study using primary epithelial cells from patients with primary ciliary dyskinesia (PCD), a disease that compromises mucociliary clearance.…”

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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“…It was envisaged that the compounds could be used as targeted NO carriers in combination with conventional antibiotics to treat chronic, β-lactamase expressing, biofilm infections ( Figure 1) [11; 12]. We have previously reported that PYRRO-C3D increases the sensitivity of non-typeable Haemophilus influenzae biofilms to treatment with azithromycin, a response that was dependent on NO-release following β-lactamase cleavage [13]. It is conceivable, however, that liberation of NO from C3Ds might also be triggered by reaction with transpeptidases/penicillin-binding proteins (PBPs) [11], the molecular target of clinical…”

Section: Accepted Manuscriptmentioning

confidence: 99%

“…*p≤0.05.A range of PYRRO-C3D concentrations (10 nM -100 µM) were tested next against mature (48 hour) in vitro S. pneumoniae biofilms. A two hour treatment time was investigated based on previous studies that demonstrated i) the response of pneumococcal biofilms to exogenous NO[7], and ii) the antimicrobial effect of PYRRO-C3D on non-influenzae biofilms[13] following 2 hour treatments. The treatment time was also chosen based on the NO release profile of PYRRO-C3D whereby little measurable NO was remaining after hours following activation(Figure 2a).…”

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confidence: 99%

Cephalosporin-NO-donor prodrug PYRRO-C3D shows β-lactam - mediated activity against Streptococcus pneumoniae biofilms

et al. 2017

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Bacterial biofilms show high tolerance towards antibiotics and are a significant problem in clinical settings where they are a primary cause of chronic infections. Novel therapeutic strategies are needed to improve anti-biofilm efficacy and support reduction in antibiotic use. Treatment with exogenous nitric oxide (NO) has been shown to modulate bacterial signaling and metabolic processes that render biofilms more susceptible to antibiotics. We previously reported on cephalosporin-3'-diazeniumdiolates (C3Ds) as NO-donor prodrugs designed to selectively deliver NO to bacterial infection sites following reaction with β-lactamases. With structures based on cephalosporins, C3Ds could, in principal, also be triggered to release NO following β-lactam cleavage mediated by transpeptidases/penicillin-binding proteins (PBPs), the antibacterial target of cephalosporin antibiotics. Transpeptidase-reactive C3Ds could potentially show both NO-mediated anti-biofilm properties and intrinsic (β-lactam-mediated) antibacterial effects. This dual-activity concept was explored using Streptococcus pneumoniae, a species that lacks β-lactamases but relies on transpeptidases for cell-wall synthesis. Treatment with PYRRO-C3D (a representative C3D containing the diazeniumdiolate NO donor PYRRO-NO) was found to significantly reduce viability of planktonic and biofilm pneumococci, demonstrating that C3Ds can elicit direct, cephalosporin-like antibacterial activity in the absence of β-lactamases. While NO release from PYRRO-C3D in the presence of pneumococci was confirmed, the anti-pneumococcal action of the compound was shown to arise exclusively from the β-lactam component and not through NO-mediated effects. The compound showed similar potency to amoxicillin against S. pneumoniae biofilms and greater efficacy than azithromycin, highlighting the potential of C3Ds as new agents for treating pneumococcal infections.

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“…It was found that PYRRO-C3D can reduce the viability of planktonic and biofilm pneumococci in the absence of β-lactamases. A study that was done to test the activity of PYRRO-C3D against a non-typeable Haemophilus influenza (NTHi) biofilms showed that PYRRO-C3D enhanced the efficacy of azithromycin against NTHi biofilms and can act as a promising adjunctive treatment for reducing biofilm-associated antibiotic tolerance [23,26].…”

Section: Enterobactin-antibiotic Conjugatesmentioning

confidence: 99%

Antibacterial Prodrugs to Overcome Bacterial Resistance

2020

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Bacterial resistance to present antibiotics is emerging at a high pace that makes the development of new treatments a must. At the same time, the development of novel antibiotics for resistant bacteria is a slow-paced process. Amid the massive need for new drug treatments to combat resistance, time and effort preserving approaches, like the prodrug approach, are most needed. Prodrugs are pharmacologically inactive entities of active drugs that undergo biotransformation before eliciting their pharmacological effects. A prodrug strategy can be used to revive drugs discarded due to a lack of appropriate pharmacokinetic and drug-like properties, or high host toxicity. A special advantage of the use of the prodrug approach in the era of bacterial resistance is targeting resistant bacteria by developing prodrugs that require bacterium-specific enzymes to release the active drug. In this article, we review the up-to-date implementation of prodrugs to develop medications that are active against drug-resistant bacteria.

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Cephalosporin-3′-Diazeniumdiolate NO Donor Prodrug PYRRO-C3D Enhances Azithromycin Susceptibility of Nontypeable Haemophilus influenzae Biofilms

Cited by 27 publications

References 47 publications

Targeting microbial biofilms: current and prospective therapeutic strategies

Targeting microbial biofilms: current and prospective therapeutic strategies

Cephalosporin-NO-donor prodrug PYRRO-C3D shows β-lactam - mediated activity against Streptococcus pneumoniae biofilms

Antibacterial Prodrugs to Overcome Bacterial Resistance

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