Indole-based Therapeutics for Patients with Pulmonary NTM Infection
At A Glance
Researchers at Colorado State University in collaboration with Creighton patented novel indole-2-carboxamide compounds for the treatment of non-tuberculous mycobacterial (NTM) infections. The development of these narrow-spectrum anti-mycobacterial drugs could revolutionize the treatment of NTM.
Non-tuberculous mycobacteria (NTM) are opportunistic pathogens, where the prevalence of NTM pulmonary infections in the United States and globally is increasing. Transmission of these pathogens may occur both from environmental sources and from person-to-person. The Mycobacterium avium complex (MAC) and Mycobacterium abscessus complex (MABSC) account for the vast majority (70-95%) of global pulmonary NTM infections. While MAC is still, overall, the most common cause of NTM infections in the US (accounting for over 70% of NTM pulmonary infections), over the last 10 years, rapidly-growing NTM of the M. abscessus complex (including the subspecies M. abscessus, M. massiliense and M. bolletii) have emerged as important human pathogens globally, causing an increasing number of pulmonary infections, especially among patients with structural lung disease such as chronic obstructive pulmonary disease, bronchiectasis and cystic fibrosis (CF).
MABSC species cause serious, life-threatening, chronic lung disease, are responsible for disseminated, often fatal, infections following lung transplantation and are associated with a higher fatality rate than any other rapidly growing mycobacteria. Of growing concern is the report that the prevalence of MABSC infections is becoming higher than that of MAC infections in CF patients worldwide, and that MABSC infections tend to target the younger CF population and those with more severe lung disease. Prevalence rates of MABSC infections among children and adult CF patients range from 5% to 48%. MABSC infection in CF patients is particularly problematic as it results in accelerated inflammatory lung damage, can be impossible to treat (with 60-70% treatment failures despite years of combination therapy), and precludes lung transplantation in many US and European centers.
MABSC species are indeed not only the most pathogenic rapidly growing mycobacteria, they are also the most antibiotic-resistant NTM. There are many factors that contribute to the drug resistance or drug tolerance of these microorganisms and as a result, the 2007 American Thoracic Society treatment guidelines cite no proven regimens to treat M. abscessus pulmonary infections. Current treatment recommendations include multidrug therapy with combinations of intravenous and oral antibiotics accompanied, in some cases, by surgical resection. Furthermore, most likely reflecting a defect in primary lung defense mechanisms, MABSC strains responsible for lung infections tend to co-occur with other pathogens such as Pseudomonas aeruginosa and Staphylococcus aureus.
- Indole-based compounds are mycobacteria-specific
- Animals models indicate efficacy against intrinsically drug resistant non-tuberculous mycobacteria
Franz, Nicholas D, et al. “Design, Synthesis and Evaluation of Indole-2-Carboxamides with Pan Anti-Mycobacterial Activity.” Bioorganic & Medicinal Chemistry, U.S. National Library of Medicine, 15 July 2017, www.ncbi.nlm.nih.gov/pubmed/28545813.
Last updated: April 2020
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#CSUInvents – #TechTuesday! In the last 10 years, rapidly-growing non- #tuberculosis mycobateria (NTM) have emerged as important human #pathogens globally, causing an increasing number of #pulmonary #infections, especially among patients with structural #lungdisease such as chronic obstructive pulmonary disease ( #COPD ), bronchiectasis and #Cysticfibrosis (CF). Researchers at Colorado State University and Creighton University have #patented #novel indole-2-carboxamide compounds for the #treatment of NTM infections. The development of these narrow-spectrum anti-mycobacterial #drugs could revolutionize the treatment of NTM.
Inventors include: Mary C. Jackson, PhD, CSU Microbiology, Immunology & Pathology, CSU College of Veterinary Medicine and Biomedical Sciences, and E. Jeffrey North, PhD, Department of Pharmacy Sciences, Creighton University.