Lipophilic Pyridinium Bisphosphonates: Potent γ<i>δ</i> T Cell Stimulators

Zhang, Yonghui; Cao, Rong; Yin, Fenglin; Lin, Fu Yang; Wang, Hong; Krysiak, Kilannin; No, Joo Hwan; Mukkamala, Dushyant; Houlihan, Kevin; Li, Jikun; Morita, Craig T.; Oldfield, Eric

doi:10.1002/anie.200905933

Cited by 62 publications

(46 citation statements)

References 39 publications

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“…The structures of the 55 compounds ( 1–55 ) tested are given in Table S2, with their dose-response curves shown in Figure S4 and their syntheses and characterization were previously reported. [3a, 16] Of the several families of compounds tested—benzoic acids, sulfonic acids, diketo acids, bisphosphonates, and dicationic species—only the lipophilic bisphosphonates were active. Representative dose-response curves for imidazolium and pyridinium bisphosphonates are shown in Figures 6 a, b, and Table S2 shows more extensive data for zoledronate ( 15 ; Figure 1) and 28 analogs (containing 1-H and 1-OH groups, and varying N-alkyl substituents).…”

Section: Resultsmentioning

confidence: 99%

Structure, Function, and Inhibition of Staphylococcus aureus Heptaprenyl Diphosphate Synthase

et al. 2016

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We report the first structure of heptaprenyl diphosphate synthase from Staphylococcus aureus (SaHepPPS), together with an investigation of its mechanism of action, and inhibition. The protein is involved in the formation of menaquinone, a key electron transporter in many bacteria, including pathogens. SaHepPPS consists of a “catalytic” subunit (SaHepPPS-2) having two “DDXXD” motifs and a “regulatory” subunit (SaHepPPS-1) that lacks these motifs. High concentrations of the substrates, isopentenyl diphosphate and farnesyl diphosphate, inhibit the enzyme, which is also potently inhibited by bisphosphonates. The most active inhibitors (Ki ~ 200 nM) were N-alkyl analogs of zoledronate containing ~C6 alkyl side-chains. They were modestly active against S. aureus cell growth, and growth inhibition was partially “rescued” by addition of menaquinone-7. Since SaHepPPS is essential for S. aureus cell growth, its structure is of interest in the context of the development of menaquinone biosynthesis inhibitors as potential antibiotic leads.

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Section: Resultsmentioning

confidence: 99%

Structure, Function, and Inhibition of Staphylococcus aureus Heptaprenyl Diphosphate Synthase

et al. 2016

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“…Examples of a successful implementation of this idea include introduction of long hydrocarbon or aromatic substituents into molecules with previously reported activity (Scheme 4) [5,25,30,31,53,54]. Interestingly, hydroxybisphosphonic analogs of bile acids appeared to be exceptionally active against L929 cells and cultures of osteoclasts.…”

Section: Scheme (3)mentioning

confidence: 99%

Physiologic Activity of Bisphosphonates – Recent Advances

Chmielewska¹,

Kafarski

2016

PHARMSCI

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“…This led to the discovery that bisphosphonates inhibited farnesyl diphosphate synthase[46] and geranylgeranyl diphosphate synthase[47], and to the development of bisphosphonates active against malaria parasites[48]. These compounds also activate gamma delta T-cells (containing the Vγ2Vδ2 T-cell receptor)[49] which can then kill bacteria[50]. …”

Section: Finding Multi-target Inhibitor Leads By Repurposing Existingmentioning

confidence: 99%

Resistance-resistant antibiotics

Oldfield

Feng

2014

Trends in Pharmacological Sciences

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112

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New antibiotics are needed because as drug resistance is increasing, the introduction of new antibiotics is decreasing. Here, we discuss six possible approaches to develop ‘resistance-resistant’ antibiotics. First, multi-target inhibitors in which a single compound inhibits more than one target may be easier to develop than conventional combination therapies with two new drugs. Second, inhibiting multiple targets in the same metabolic pathway is expected to be an effective strategy due to synergy. Third, discovering multiple-target inhibitors should be possible by using sequential virtual screening. Fourth, re-purposing existing drugs can lead to combinations of multi-target therapeutics. Fifth, targets need not be proteins. Sixth, inhibiting virulence factor formation and boosting innate immunity may also lead to decreased susceptibility to resistance. Although it is not possible to eliminate resistance, the approaches reviewed here offer several possibilities for reducing the effects of mutations and in some cases suggest that sensitivity to existing antibiotics may be restored, in otherwise drug resistant organisms.

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Lipophilic Pyridinium Bisphosphonates: Potent γδ T Cell Stimulators

Cited by 62 publications

References 39 publications

Structure, Function, and Inhibition of Staphylococcus aureus Heptaprenyl Diphosphate Synthase

Structure, Function, and Inhibition of Staphylococcus aureus Heptaprenyl Diphosphate Synthase

Physiologic Activity of Bisphosphonates – Recent Advances

Resistance-resistant antibiotics

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