Halogenated Pyrrolopyrimidines with Low MIC on Staphylococcus aureus and Synergistic Effects with an Antimicrobial Peptide

Olsen, Cecilie Elisabeth; Blindheim, Fredrik Heen; Søgaard, Caroline Krogh; Røst, Lisa Marie; Singleton, Amanda Holstad; Bergum, Olaug Elisabeth Torheim; Bruheim, Per; Otterlei, Marit; Sundby, Eirik; Hoff, Bård Helge

doi:10.3390/antibiotics11080984

Cited by 7 publications

(14 citation statements)

References 49 publications

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“…To produce 6‐aryl‐4‐benzyl‐7 H ‐pyrrolo[2,3‐ d ]pyrimidines for biological studies, the dihalogenated building block 35 was synthesized following a previously reported procedure (Scheme 4). [20] The C‐6 position could be chemoselectively arylated by Suzuki–Miyaura cross‐coupling conditions giving 36 . Negishi cross‐coupling on pyrrolopyrimidine 36 was performed using a selection of substituted benzyl bromides with Pd(PPh 3 ) 4 as catalyst in THF at 60 °C (Scheme 4).…”

Section: Resultsmentioning

confidence: 99%

Negishi Cross‐Coupling in the Preparation of Benzyl Substituted Pyrrolo[2,3‐d]pyrimidine Based CSF1R Inhibitors

et al. 2023

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The colony-stimulating factor 1 receptor (CSF1R) is a protein kinase emerging as an attractive target with clinical relevance in cancer, CNS and inflammatory diseases. Molecular docking experiments followed by synthesis and structure-activity relationship have been used to identify low molecular weight structures as promising hits for lead optimization. These molecules are synthesized from a 4-chloro-6-iodo-pyrrolo[2,3-d]pyrimidine building block using Negishi and Suzuki-Miyaura cross-coupling reactions in high yields. Several inhibitors possessed excellent enzymatic potency, and the parent compound preferably binds to the autoinhibited form of CSF1R. Cellular and in vivo profiling indicate that further tuning of drug structure is needed prior to efficacy studies.

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Section: Resultsmentioning

confidence: 99%

Negishi Cross‐Coupling in the Preparation of Benzyl Substituted Pyrrolo[2,3‐d]pyrimidine Based CSF1R Inhibitors

et al. 2023

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“…A putative Tmk inhibitor called JK-274 ( Figure 2A ) was previously found to have a low MIC (20 μM, 8 μg/mL) toward S. aureus . When combined with a ½ MIC BTP-001 (2 μM, 8 μg/mL), the MIC for JK-274 was reduced 8-fold ( Olsen et al, 2022 ). In this study, we wanted to investigate the molecular basis of the individual and combined effects of JK-274 and BTP-001 by using signalomics supplemented with metabolomics.…”

Section: Resultsmentioning

confidence: 99%

“…All concentrations are given as net peptide concentrations and 4 μg/mL equals approximately 1 μM. The halogenated pyrrolopyrimidine JK-274 (( R )-4-(4-((1-(4-bromophenyl)ethyl)amino) - 7 H- pyrrolo[ 2,3-d ]pyrimidin-6-yl)phenol) was synthesized as previously described and 4 μg/mL is approximately equal to 10 μM ( Olsen et al, 2022 ). JK-274 was dissolved in DMSO and stored at 4°C.…”

Section: Methodsmentioning

confidence: 99%

“…Biofilm studies demonstrated that BTP-001 eradicates existing biofilms and prevents biofilm formation in Staphylococcus epidermidis , and that it showed promise for use in bone cement to prevent prosthetic joint infection ( Raeder et al, 2021 ). In addition, a recent study showed a strong additive effect of BTP-001 combined with a brominated pyrrolopyrimidine called JK-274 in Staphylococcus aureus ( Olsen et al, 2022 ). The structure of JK-274 resembles that of known thymidylate monophosphate kinase (Tmk) inhibitors and has inhibitory activity against Escherichia coli Tmk in enzymatic assays ( Blindheim et al, 2021a ; Olsen et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

“…In addition, a recent study showed a strong additive effect of BTP-001 combined with a brominated pyrrolopyrimidine called JK-274 in Staphylococcus aureus ( Olsen et al, 2022 ). The structure of JK-274 resembles that of known thymidylate monophosphate kinase (Tmk) inhibitors and has inhibitory activity against Escherichia coli Tmk in enzymatic assays ( Blindheim et al, 2021a ; Olsen et al, 2022 ). Combining the two drug candidates yielded an 8-fold reduction in the minimal inhibitory concentration (MIC) of JK-274 in S. aureus ( Olsen et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

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Activation of multiple stress responses in Staphylococcus aureus substantially lowers the minimal inhibitory concentration when combining two novel antibiotic drug candidates

Singleton,

Bergum,

Søgaard

et al. 2023

Front. Microbiol.

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The past few decades have been plagued by an increasing number of infections caused by antibiotic resistant bacteria. To mitigate the rise in untreatable infections, we need new antibiotics with novel targets and drug combinations that reduce resistance development. The novel β-clamp targeting antimicrobial peptide BTP-001 was recently shown to have a strong additive effect in combination with the halogenated pyrrolopyrimidine JK-274. In this study, the molecular basis for this effect was examined by a comprehensive proteomic and metabolomic study of the individual and combined effects on Staphylococcus aureus. We found that JK-274 reduced activation of several TCA cycle enzymes, likely via increasing the cellular nitric oxide stress, and BTP-001 induced oxidative stress in addition to inhibiting replication, translation, and DNA repair processes. Analysis indicated that several proteins linked to stress were only activated in the combination and not in the single treatments. These results suggest that the strong additive effect is due to the activation of multiple stress responses that can only be triggered by the combined effect of the individual mechanisms. Importantly, the combination dose required to eradicate S. aureus was well tolerated and did not affect cell viability of immortalized human keratinocyte cells, suggesting a species-specific response. Our findings demonstrate the potential of JK-274 and BTP-001 as antibiotic drug candidates and warrant further studies.

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Halogenated Antimicrobial Agents to Combat Drug-Resistant Pathogens

Faleye,

Boya,

Lee

et al. 2023

Pharmacol Rev

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Antimicrobial resistance presents us with a potential global crisis as it undermines the abilities of conventional antibiotics to combat pathogenic microbes. The history of antimicrobial agents is replete with examples of scaffolds containing halogens. In this review, we discuss the impacts of halogen atoms in various antibiotic types and antimicrobial scaffolds and their modes of action, structure-activity relationships, and the contributions of halogen atoms in antimicrobial activity and drug resistance. Other halogenated molecules, including carbohydrates, peptides, lipids, and polymeric complexes, are also reviewed, and the effects of halogenated scaffolds on pharmacokinetics, pharmacodynamics, and factors affecting antimicrobial and antivirulence activities are presented. Furthermore, the potential of halogenation to circumvent antimicrobial resistance and rejuvenate impotent antibiotics is addressed. This review provides an overview of the significance of halogenation, the abilities of halogens to interact in biomolecular settings and enhance pharmacological properties, and their potential therapeutic usages in preventing a post-antibiotic era. Significance StatementAntimicrobial resistance and the increasing impotence of antibiotics are critical threats to global health. The roles and importance of halogen atoms in antimicrobial drug scaffolds have been established, but comparatively little is known of their pharmacological impacts on drug resistance and antivirulence activities. This review is the first to extensively evaluate the roles of halogen atoms in various antibiotic classes and pharmacological scaffolds and to provide an overview of their abilities to overcome antimicrobial resistance.

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Halogenated Pyrrolopyrimidines with Low MIC on Staphylococcus aureus and Synergistic Effects with an Antimicrobial Peptide

Cited by 7 publications

References 49 publications

Negishi Cross‐Coupling in the Preparation of Benzyl Substituted Pyrrolo[2,3‐d]pyrimidine Based CSF1R Inhibitors

Negishi Cross‐Coupling in the Preparation of Benzyl Substituted Pyrrolo[2,3‐d]pyrimidine Based CSF1R Inhibitors

Activation of multiple stress responses in Staphylococcus aureus substantially lowers the minimal inhibitory concentration when combining two novel antibiotic drug candidates

Halogenated Antimicrobial Agents to Combat Drug-Resistant Pathogens

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