Abstract To address the emergence and spread of multi‐drug resistant tuberculosis, a novel semisynthetic series of spectinomycin analogs was generated with bacterial selective ribosomal inhibition and excellent narrow‐spectrum antitubercular activity. These analogs, the spectinamides, lack cross‐ resistance with existing tuberculosis therapeutics, maintain activity against MDR‐ and XDR‐ tuberculosis, retain spectinomycin’s high selectivity index, and synergistically reduce lung bacterial burdens in chronic in vivo mouse models when used in combination with other TB therapies. The potent antitubercular and selective properties of spectinamides is the result of their ability to avoid intrinsic efflux by the Rv1258c pump, demonstrating that synthetic modifications to classical antibiotics can overcome the challenge of intrinsic efflux pump‐mediated resistance. Detailed SAR has been developed for protein synthesis inhibition and efflux avoidance, pharmacokinetics, and in vivo efficacy of the spectinamides. The most notable result is the synergy observed when spectinamides are combined with rifampin and pyrazinamide in C3HeB/FeJ mice bearing tubercular lesions with similar pathology to those found in humans. In this renewal, we aim focus the development of the spectinamides as combination agents capable of working synergistically with other TB agents to clear infections in necrotic lesions through 3 iterative aims: (i) Combination studies. The goal of this aim is to evaluate and define spectinamide combination treatments that specifically target synergistic activity in the necrotic granuloma. (ii) Generation of second generation antitubercular spectinomycin analogs. The design and synthesis of the next generation of spectinomycin antitubercular antibiotics with the primary goal of increasing the therapeutic window of lead compounds via improved host tolerability, bioavailability, distribution into the granuloma, and efflux avoidance. (iii) Evaluation of second generation spectinamides – Compounds synthesized in aim 2 will progress through three iterative stages of tests that include microbial assessment, pharmacokinetic testing, toxicologic and in vivo efficacy experiments.