作者: Lukka, Pradeep B. ; Lee, Richard E. ; Zimmerman, Matthew D ; Wang, Han ; Böttger, Erik C. ; Robertson, Gregory T ; Meibohm, Bernd ; Lee, Robin B ; Lukka, Pradeep B ; Parmar, Keyur R ; Lee, Robin B. ; Dartois, Vêronique ; Lenaerts, Anne J ; Parmar, Keyur R. ; Lee, Richard E ; Scherbakov, Dimitri ; Liu, Jiuyu ; Lenaerts, Anne J. ; Ektnitphong, Victoria A. ; Ektnitphong, Victoria A ; Böttger, Erik C ; Robertson, Gregory T. ; Wagh, Santosh ; Lu, Yan

Spectinamides are a novel class of narrow-spectrum antitubercular agents with the potential to treat drug-resistant tuberculosis infections. Spectinamide 1810 has shown a good safety record following subcutaneous injection in mice or infusion in rats but exhibits transient acute toxicity following bolus administration in either species. To improve the therapeutic index of 1810, an injectable prodrug strategy was explored. The injectable phosphate prodrug 3408 has a superior maximum tolerated dose compared to 1810 or Gentamicin. Following intravenous administration in rodents, prodrug 3408 was quickly converted to 1810. The resulting 1810 exposure and pharmacokinetic profile after 3408 administration was identical to equivalent molar amounts of 1810 given directly by intravenous administration. 3408 and the parent 1810 exhibited similar overall efficacy in a BALB/c acute tuberculosis efficacy model. Delivery of 1810 in phosphate prodrug form, therefore, holds the potential to improve further the therapeutic index of an already promising tuberculosis antibiotic.

2024-09-01·The Journal of Antibiotics

Synthesis and antibacterial action of 3’,6’-disubstituted spectinomycins

Article

作者: Selchow, Petra ; Dunn, Christine M ; Wilt, Laura A ; Lee, Richard E ; Snoke, Hannah E ; Sander, Peter ; Hobbie, Sven N ; Murphy, Patricia A ; Dharuman, Suresh ; Böttger, Erik C ; Phelps, Gregory A ; Lee, Robin B ; Haldimann, Klara

AbstractSpectinomycin is an aminocyclitol antibiotic with a unique ribosomal binding site. Prior synthetic modifications of spectinomycin have enhanced potency and antibacterial spectrum through addition at the 6’-position to produce trospectomycin and to the 3’-position to produce spectinamides and aminomethyl spectinomycins. This study focused on the design, synthesis, and evaluation of three 3’,6’-disubstituted spectinomycin analogs: trospectinamide, N-benzyl linked aminomethyl, and N-ethylene linked aminomethyl trospectomycins. Computational experiments predicted that these disubstituted analogs would be capable of binding within the SPC ribosomal binding site. The new analogs were synthesized from trospectomycin, adapting the previously established routes for the spectinamide and aminomethyl spectinomycin series. In a cell-free translation assay, the disubstituted analogs showed ribosomal inhibition similar to spectinomycin or trospectomycin. These disubstituted analogs demonstrated inhibitory MIC activity against various bacterial species with the 3’-modification dictating spectrum of activity, leading to improved activity against mycobacterium species. Notably, N-ethylene linked aminomethyl trospectomycins exhibited increased potency against Mycobacterium abscessus and trospectinamide displayed robust activity against M. tuberculosis, aligning with the selective efficacy of spectinamides. The study also found that trospectomycin is susceptible to efflux in M. tuberculosis and M. abscessus. These findings contribute to the understanding of the structure-activity relationship of spectinomycin analogs and can guide the design and synthesis of more effective spectinomycin compounds.

2023-06-17·Pharmaceutics

Development of a Minimalistic Physiologically Based Pharmacokinetic (mPBPK) Model for the Preclinical Development of Spectinamide Antibiotics.

Article

作者: Robertson, Gregory T ; Gonzalez-Juarrero, Mercedes ; Liu, Jiuyu ; Edginton, Andrea ; Braunstein, Miriam ; Temrikar, Zaid H ; Hickey, Anthony J ; Wagh, Santosh ; Parmar, Keyur R ; Meibohm, Bernd ; Lukka, Pradeep B ; Lee, Richard E

Spectinamides 1599 and 1810 are lead spectinamide compounds currently under preclinical development to treat multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis. These compounds have previously been tested at various combinations of dose level, dosing frequency, and route of administration in mouse models of Mycobacterium tuberculosis (Mtb) infection and in healthy animals. Physiologically based pharmacokinetic (PBPK) modeling allows the prediction of the pharmacokinetics of candidate drugs in organs/tissues of interest and extrapolation of their disposition across different species. Here, we have built, qualified, and refined a minimalistic PBPK model that can describe and predict the pharmacokinetics of spectinamides in various tissues, especially those relevant to Mtb infection. The model was expanded and qualified for multiple dose levels, dosing regimens, routes of administration, and various species. The model predictions in mice (healthy and infected) and rats were in reasonable agreement with experimental data, and all predicted AUCs in plasma and tissues met the two-fold acceptance criteria relative to observations. To further explore the distribution of spectinamide 1599 within granuloma substructures as encountered in tuberculosis, we utilized the Simcyp granuloma model combined with model predictions in our PBPK model. Simulation results suggest substantial exposure in all lesion substructures, with particularly high exposure in the rim area and macrophages. The developed model may be leveraged as an effective tool in identifying optimal dose levels and dosing regimens of spectinamides for further preclinical and clinical development.

100 项与 Spectinamides 相关的药物交易

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