作者: Meibohm, Bernd ; Zimmerman, Matthew D. ; Jones, Isabelle L. ; Hastings, Courtney ; Bauman, Allison A. ; Dartois, Veronique ; Brooks, Elizabeth J. ; Ramey, Michelle E. ; Massoudi, Lisa M. ; Kaya, Firat ; Waidyarachchi, Samanthi L. ; Liu, Jiuyu ; Robertson, Gregory T. ; Gonzalez-Juarrero, Mercedes ; Lenaerts, Anne J. ; Bowlin, Terry L. ; Xie, Min ; Lee, Richard E. ; Maclaughlin, Madelyn R. ; Sarathy, Jansy P. ; Butler, Michelle M. ; Benedict, Noalani D. ; Scherman, Michael S. ; Miller-Dawson, Jake A. ; Lyons, Michael A.

ABSTRACT The spectinamides are novel, narrow-spectrum semisynthetic analogs of spectinomycin, modified to avoid intrinsic efflux by Mycobacterium tuberculosis . Spectinamides, including lead MBX-4888A (Lee-1810), exhibit promising therapeutic profiles in mice, as single drugs and as partner agents with other anti-tuberculosis antibiotics including rifampin and/or pyrazinamide. Here, we show that MBX-4888A, given by injection with the front-line standard of care regimen, is treatment shortening in multiple murine tuberculosis infection models. The positive treatment responses to MBX-4888A combination therapy in multiple mouse models, including mice exhibiting advanced pulmonary disease, can be attributed to favorable distribution in tissues and lesions, retention in caseum, along with favorable effects with rifampin and pyrazinamide under conditions achieved in necrotic lesions. This study also provides an additional data point regarding the safety and tolerability of spectinamide MBX-4888A in long-term murine efficacy studies.

2024-11-01·Bioorganic & Medicinal Chemistry Letters

Enhancing the therapeutic window for Spectinamide anti-tuberculosis Agents: Synthesis, Evaluation, and activation of phosphate prodrug 3408

Article

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

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.

100 项与 Spectinamides 相关的药物交易

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