# Novel Spectinamide Antibiotics for the Treatment of MDR/XDR Tuberculosis

> **NIH NIH R44** · MICROBIOTIX, INC · 2020 · $1,000,000

## Abstract

Summary/Abstract
 The overall objective of this project is to develop a novel chemical class of tuberculosis (TB) therapeutic
agents, the spectinamide series, for use against MDR and XDR strains of Mycobacterium tuberculosis (Mtb) and
identify, through a series of in vivo efficacy assays and preclinical pharmacokinetics, toxicology and safety
pharmacology studies, a clinical candidate. TB is a lethal infectious disease, second only to HIV/AIDS as a
cause of death. Estimates by the World Health Organization show one-quarter of the world population is infected
with Mtb, the bacterium that causes TB; approximately 10% of infected individuals will develop active TB at some
time in their lives. Of recent concern is the rising number of TB cases involving strains that are multidrug-
resistant (MDR), which is defined as being resistant to treatment with isoniazid and rifampicin, the two first-line
antibiotics for TB therapy and those that are extensively drug-resistant tuberculosis [XDR TB; defined as being
resistant to isoniazid and rifampicin (as for MDR TB) and also to any fluoroquinolone and at least one of the
three injectable second-line drugs (i.e., amikacin, kanamycin, or capreomycin)]. Treatment options for
MDR/XDR TB include the two remaining first-line agents, ethambutol and pyrazinamide, second-line agents to
which the strain is not resistant, such as streptomycin, as well as unproven agents such as linezolid,
amoxicillin/clavulanate, clarithromycin, clofazimine and imipenem. Research suggests that at least four drugs
and 18-24 month duration of treatment may be required for successful therapy of XDR TB; however, toxicity of
the agents may preclude patients from being effectively treated. There is a clear unmet medical need for
efficacious and safe drugs to be used as treatment for MDR/XDR TB. As demonstrated in Phase I of the project,
the novel spectinomycin analog and key spectinamides, possess potent in vitro activity against MDR/XDR TB,
demonstrate efficacy in both acute and subacute murine models of TB infection, and are safe compounds,
displaying low in vitro cytotoxicity and no observed in vivo toxicity. In Phase II, we identified MBX 4888 as the
preclinical candidate, with similar efficacy to other lead compounds but with an improved safety profile. In Phase
IIb, we will, in conjunction with our collaborators, Drs. Richard Lee, Greg Robertson and Anne Lenaerts, continue
to evaluate in vivo efficacy in mice (inhalational dosing). We will also conduct pharmacokinetic studies, GLP
toxicology and safety pharmacology studies in two species as well as manufacturing of non-GMP and GMP lots
of material sufficient to complete preclinical and Phase I clinical studies. Finally, we will schedule a pre-IND
meeting with the FDA and the South African authorities in preparation for an IND filing. In Phase III, we will meet
all remaining FDA requirements, continue to explore alternative routes of administration such as inhalational,
write an IND appl...

## Key facts

- **NIH application ID:** 10000004
- **Project number:** 5R44AI098271-07
- **Recipient organization:** MICROBIOTIX, INC
- **Principal Investigator:** Michelle M. Butler
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,000,000
- **Award type:** 5
- **Project period:** 2012-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10000004

## Citation

> US National Institutes of Health, RePORTER application 10000004, Novel Spectinamide Antibiotics for the Treatment of MDR/XDR Tuberculosis (5R44AI098271-07). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10000004. Licensed CC0.

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