Design, synthesis and biological evaluation of a halogenated phenazine-erythromycin conjugate prodrug for antibacterial applications

Yang, Hongfen; Liu, Ke; Jin, Shouguang; Huigens, Robert W.

doi:10.1039/d0ob02428g

Cited by 15 publications

(27 citation statements)

References 22 publications

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“…By comparison, previous studies which focused solely on bacterial resistance to the parent form of antibiotics yielded parameters that may not apply to prodrug forms. For example, the minimum inhibitory concentration (MIC) is commonly used as a parameter for resistance (Brauner et al , 2016 ), yet the MIC of the parent and pro‐forms of the same drug can differ, as seen with both model prodrugs used in this study as well as others from the literature (Wang et al , 2018 ; Evans et al , 2019 ; Yang et al , 2021 ). Using existing MIC classifications, these prodrugs could have been labeled ineffective; yet, our experiments showed that different environmental conditions or, in the case of AMP prodrugs, linker sequences, may result in success.…”

Section: Discussionmentioning

confidence: 96%

“…For example, agent‐based simulations revealed that the rate of prodrug activation (i.e., catalytic efficiency, k cat / K M ) had a strong effect on the MIC of each compound (Murphy et al , 2011 ). Furthermore, empirical studies have found there to be differences in MIC between parent and prodrug forms, as well as higher variance in prodrug MIC across bacterial strains, relative to the parent drug (Wang et al , 2018 ; Evans et al , 2019 ; Yang et al , 2021 ).…”

Section: Introductionmentioning

confidence: 99%

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Dimensionless parameter predicts bacterial prodrug success

Holt

Tuttle

et al. 2022

Molecular Systems Biology

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Understanding mechanisms of antibiotic failure is foundational to combating the growing threat of multidrug‐resistant bacteria. Prodrugs—which are converted into a pharmacologically active compound after administration—represent a growing class of therapeutics for treating bacterial infections but are understudied in the context of antibiotic failure. We hypothesize that strategies that rely on pathogen‐specific pathways for prodrug conversion are susceptible to competing rates of prodrug activation and bacterial replication, which could lead to treatment escape and failure. Here, we construct a mathematical model of prodrug kinetics to predict rate‐dependent conditions under which bacteria escape prodrug treatment. From this model, we derive a dimensionless parameter we call the Bacterial Advantage Heuristic ( BAH ) that predicts the transition between prodrug escape and successful treatment across a range of time scales (1–10 4 h), bacterial carrying capacities (5 × 10 4 –10 5 CFU/µl), and Michaelis constants ( K M = 0.747–7.47 mM). To verify these predictions in vitro , we use two models of bacteria‐prodrug competition: (i) an antimicrobial peptide hairpin that is enzymatically activated by bacterial surface proteases and (ii) a thiomaltose‐conjugated trimethoprim that is internalized by bacterial maltodextrin transporters and hydrolyzed by free thiols. We observe that prodrug failure occurs at BAH values above the same critical threshold predicted by the model. Furthermore, we demonstrate two examples of how failing prodrugs can be rescued by decreasing the BAH below the critical threshold via (i) substrate design and (ii) nutrient control. We envision such dimensionless parameters serving as supportive pharmacokinetic quantities that guide the design and administration of prodrug therapeutics.

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Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Dimensionless parameter predicts bacterial prodrug success

Holt

Tuttle

et al. 2022

Molecular Systems Biology

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“…12 Phenazine derivatives 4-6 displayed antiviral activity against bovine viral diarrhea virus (Figure 1). 13 Moreover, phenazine scaffold is also used in other research fields, for example, its conjugation with erythromycin as a prodrug for antibacterial applications, 14 and being used in biosensor and materials. 15,16…”

Section: Antiviral Alkaloids and Alkaloid-like Compounds From Commonl...mentioning

confidence: 99%

“…Structure of a drug ceftazidime (13), an inhibitor of viral spike protein-ACE2 interaction GRL0617 ( 14) is an antiviral drug lead, and it was found to be a noncovalent class of papain-like protease (PLpro) inhibitor of SARS-CoV virus (Figure 4). 21 Among the library of 50,080 compounds, GRL0617 (14) was found to be the most potent PLpro inhibitor, and it was co-recrystallized with the enzyme PLpro.…”

Section: Figure 1 Antiviral Phenazine Derivatives 1-6mentioning

confidence: 99%

Alkaloids and Alkaloid-Like Compounds are Potential Scaffolds of Antiviral Agents against SARS-CoV-2 (COVID-19) Virus

Kittakoop¹,

Darshana²,

Sangsuwan³

et al. 2022

HETEROCYCLES

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COVID-19 pandemic has an enormous impact on humans, and it has disrupted daily life of people. Moreover, COVID-19 pandemic has significant negative effects on the world economics. To prevent the viral infection, vaccines are rapidly developed and available for certain strains of SARS-CoV-2 virus.However, the emerging of new variants has caused the problems for COVID-19 vaccines due to immune escape ability, challenging the vaccine development process which usually takes years. In this regard, there is a critical need of new antiviral compounds that can be used to combat SARS-CoV-2 virus safely and effectively. This review provides an overview on alkaloids and alkaloid-like compounds, which have antiviral activity against SARS-CoV-2 virus and related coronaviruses. Drug repurposing has played a crucial role for the drug discovery of COVID-19, and many effective antiviral agents against SARS-CoV-2 virus are from commonly used drugs or antiviral leads. Antiviral natural alkaloids and derivatives, which have the activity toward SARS-CoV-2 virus and related coronaviruses, are also discussed in this review.

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“…Here, antimicrobials can be linked to antibodies, peptides, or various compounds to improve (i) target specificity, (ii) penetration of the biofilm matrix, or (iii) condition-specific activity [ 162 , 163 , 164 , 165 , 166 , 167 , 168 ]. This approach can reduce the efficacy of biofilms’ protective and resistant nature when challenged by traditional antibiotics and has found success in recent studies and clinical trials [ 169 , 170 , 171 ].…”

Section: Therapeutic Drug Conjugatesmentioning

confidence: 99%

Strategies and Approaches for Discovery of Small Molecule Disruptors of Biofilm Physiology

et al. 2021

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Biofilms, the predominant growth mode of microorganisms, pose a significant risk to human health. The protective biofilm matrix, typically composed of exopolysaccharides, proteins, nucleic acids, and lipids, combined with biofilm-grown bacteria’s heterogenous physiology, leads to enhanced fitness and tolerance to traditional methods for treatment. There is a need to identify biofilm inhibitors using diverse approaches and targeting different stages of biofilm formation. This review discusses discovery strategies that successfully identified a wide range of inhibitors and the processes used to characterize their inhibition mechanism and further improvement. Additionally, we examine the structure–activity relationship (SAR) for some of these inhibitors to optimize inhibitor activity.

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Design, synthesis and biological evaluation of a halogenated phenazine-erythromycin conjugate prodrug for antibacterial applications

Abstract: We report the synthesis and initial biological assessment of a halogenated phenazine–erythromycin conjugate prodrug 5 aimed to treat bacterial infections.

Cited by 15 publications

References 22 publications

Dimensionless parameter predicts bacterial prodrug success

Dimensionless parameter predicts bacterial prodrug success

Alkaloids and Alkaloid-Like Compounds are Potential Scaffolds of Antiviral Agents against SARS-CoV-2 (COVID-19) Virus

Strategies and Approaches for Discovery of Small Molecule Disruptors of Biofilm Physiology

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