Antimicrobial agents and chemotherapy · 2024
Spectinamide MBX-4888A exhibits favorable lesion and tissue distribution and promotes treatment shortening in advanced murine models of tuberculosis.
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Bauman Allison A, Sarathy Jansy P, Kaya Firat, Massoudi Lisa M, Scherman Michael S, Hastings Courtney, Liu Jiuyu, Xie Min, Brooks Elizabeth J, Ramey Michelle E, Jones Isabelle L, Benedict Noalani D, Maclaughlin Madelyn R, Miller-Dawson Jake A, Waidyarachchi Samanthi L, Butler Michelle M, Bowlin Terry L, Zimmerman Matthew D, Lenaerts Anne J, Meibohm Bernd, Gonzalez-Juarrero Mercedes, Lyons Michael A, Dartois Veronique, Lee Richard E, Robertson Gregory T
Аннотация
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.