# Development of Novel Proteins Synthesis Inhibitors for MDR Tuberculosis

> **NIH NIH R01** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2020 · $811,999

## Abstract

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.

## Key facts

- **NIH application ID:** 9880377
- **Project number:** 5R01AI090810-08
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Richard E. Lee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $811,999
- **Award type:** 5
- **Project period:** 2010-07-06 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9880377

## Citation

> US National Institutes of Health, RePORTER application 9880377, Development of Novel Proteins Synthesis Inhibitors for MDR Tuberculosis (5R01AI090810-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9880377. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*